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1
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Vázquez Marrero VR, Dresler M, Haggadone MD, Lu A, Shin S. GM-CSF engages multiple signaling pathways to enhance pro-inflammatory cytokine responses in human monocytes during Legionella infection. Infect Immun 2025:e0056524. [PMID: 40470942 DOI: 10.1128/iai.00565-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/29/2025] [Indexed: 06/11/2025] Open
Abstract
The proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for host defense against a wide range of pathogens. During infection with the intracellular bacterial pathogen Legionella pneumophila, we previously found that GM-CSF enhances inflammatory cytokine production in murine monocytes and is required for in vivo control of Legionella. It is unclear whether GM-CSF similarly augments cytokine production in human monocytes during bacterial infection. Here, we find that GM-CSF enhances inflammatory cytokine expression in Legionella-infected human monocytes by engaging multiple signaling pathways. Legionella- and Toll-like receptor-dependent NF-[Formula: see text]B signaling is a prerequisite signal for GM-CSF to promote cytokine expression. Then, GM-CSF-driven Janus kinase 2/signal transducer and activator of transcription 5 signaling is required to augment cytokine expression in Legionella-infected human monocytes. We also found a role for phosphatidylinositol-3-kinase/Akt/mTORC1 signaling in GM-CSF-dependent upregulation of cytokine expression. Finally, glycolysis and amino acid metabolism are also critical for GM-CSF to boost cytokine gene expression. Our findings show that GM-CSF-mediated enhancement of cytokine expression in infected human monocytes is regulated by multiple signaling pathways, thereby allowing the host to fine-tune antibacterial immunity.
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Affiliation(s)
- Víctor R Vázquez Marrero
- Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Madison Dresler
- Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Biological Sciences, Mount Holyoke College, South Hadley, Massachusetts, USA
| | - Mikel D Haggadone
- Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Allyson Lu
- Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Sunny Shin
- Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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2
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Tadepalli S, Clements DR, Raquer-McKay HM, Lüdtke A, Saravanan S, Seong D, Vitek L, Richards CM, Carette JE, Mack M, Gottfried-Blackmore A, Graves EE, Idoyaga J. CD301b+ monocyte-derived dendritic cells mediate resistance to radiotherapy. J Exp Med 2025; 222:e20231717. [PMID: 40146036 PMCID: PMC11949126 DOI: 10.1084/jem.20231717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/14/2024] [Accepted: 02/14/2025] [Indexed: 03/28/2025] Open
Abstract
Monocytes infiltrating tumors acquire various states that distinctly impact cancer treatment. Here, we show that resistance of tumors to radiotherapy (RT) is controlled by the accumulation of monocyte-derived dendritic cells (moDCs). These moDCs are characterized by the expression of CD301b and have a superior capacity to generate regulatory T cells (Tregs). Accordingly, moDC depletion limits Treg generation and improves the therapeutic outcome of RT. Mechanistically, we demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF) derived from radioresistant tumor cells following RT is necessary for the accumulation of moDCs. Our results unravel the immunosuppressive function of moDCs and identify GM-CSF as an immunotherapeutic target during RT.
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Affiliation(s)
- Sirimuvva Tadepalli
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Immunology Program, Stanford University School of Medicine, Stanford, CA, USA
- Department of Radiation Oncology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA
| | - Derek R. Clements
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Immunology Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Hayley M. Raquer-McKay
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Immunology Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Anja Lüdtke
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Immunology Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Sanjana Saravanan
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Immunology Program, Stanford University School of Medicine, Stanford, CA, USA
| | - David Seong
- Immunology Program, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Lorraine Vitek
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Christopher M. Richards
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jan E. Carette
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Matthias Mack
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Andres Gottfried-Blackmore
- Department of Pharmacology, University of California San Diego School of Medicine, San Diego, CA, USA
- Department of Medicine, Division of Gastroenterology, University of California San Diego School of Medicine, San Diego, CA, USA
- Gastroenterology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
| | - Edward E. Graves
- Department of Radiation Oncology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA
| | - Juliana Idoyaga
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Immunology Program, Stanford University School of Medicine, Stanford, CA, USA
- Department of Pharmacology, University of California San Diego School of Medicine, San Diego, CA, USA
- Department of Molecular Biology, University of California San Diego School of Biological Sciences, San Diego, CA, USA
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3
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Lu Y, Ma N, Cheng K, Liu G, Liang J, Xu C, Li D, Cao C, Gao X, Chen L, Wang X, Wang Y, Zhao X, Jiang K. An OMV-Based Nanovaccine as Antigen Presentation Signal Enhancer for Cancer Immunotherapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2413392. [PMID: 39811977 DOI: 10.1002/adma.202413392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 01/07/2025] [Indexed: 01/16/2025]
Abstract
Antigen-presenting cells (APCs) process tumor vaccines and present tumor antigens as the first signals to T cells to activate anti-tumor immunity, which process requires the assistance of co-stimulatory second signals on APCs. The immune checkpoint programmed death ligand 1 (PD-L1) not only mediates the immune escape of tumor cells but also acts as a co-inhibitory second signal on APCs. The serious dysfunction of second signals due to the high expression of PD-L1 on APCs in the tumor body results in the inefficiency of tumor vaccines. To overcome this challenge, a previously established Plug-and-Display tumor vaccine platform based on bacterial outer membrane vesicles (OMVs) is developed into an "Antigen Presentation Signal Enhancer" (APSE) by surface-modifying PD-L1 antibodies (αPD-L1). While delivering tumor antigens, APSE can activate the expression of co-stimulatory second signals in APCs due to the high immunogenicity of OMVs. More importantly, the surface-modified αPD-L1 binds to the co-inhibitory signals PD-L1, potentially restoring CD80 function and ensuring efficient co-stimulatory second signals and activation of anti-tumor immunity. The results reveal the importance of PD-L1 blockage in the initiation process of anti-tumor immunity, and the second signal modulation capability of APSE can expand the application potential of cancer vaccines to less immunogenic malignancies.
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Affiliation(s)
- Yichao Lu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, China
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No.11 Zhongguancun Beiyitiao, Beijing, 100190, China
- IGDB-NCNST Joint Research Center, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Nana Ma
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No.11 Zhongguancun Beiyitiao, Beijing, 100190, China
- IGDB-NCNST Joint Research Center, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Keman Cheng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No.11 Zhongguancun Beiyitiao, Beijing, 100190, China
- IGDB-NCNST Joint Research Center, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Guangna Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No.11 Zhongguancun Beiyitiao, Beijing, 100190, China
- IGDB-NCNST Joint Research Center, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Jie Liang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No.11 Zhongguancun Beiyitiao, Beijing, 100190, China
- IGDB-NCNST Joint Research Center, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Chen Xu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, China
| | - Danrui Li
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, China
| | - Cheng Cao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, China
| | - Xiaoyu Gao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No.11 Zhongguancun Beiyitiao, Beijing, 100190, China
- IGDB-NCNST Joint Research Center, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Liting Chen
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, China
| | - Xinwei Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No.11 Zhongguancun Beiyitiao, Beijing, 100190, China
- IGDB-NCNST Joint Research Center, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yazhou Wang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, China
| | - Xiao Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No.11 Zhongguancun Beiyitiao, Beijing, 100190, China
- IGDB-NCNST Joint Research Center, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Kuirong Jiang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, China
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Nabi R, Chouljenko VN, Musarrat F, Davis ME, Mohan H, Ghavimi R, Stanfield B, Dutta O, Kousoulas KG. The Novel Oncolytic Herpes Simplex Virus Type-1 (HSV-1) Vaccine Strain VC2 Constitutively Expressing GM-CSF Causes Increased Intratumoral T Cell Infiltration and Inhibition of Tumor Metastasis in the 4T1/Balb/c Mouse Model of Stage Four Breast Cancer. J Med Virol 2025; 97:e70220. [PMID: 39930884 DOI: 10.1002/jmv.70220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 01/24/2025] [Accepted: 01/26/2025] [Indexed: 05/08/2025]
Abstract
Oncolytic virotherapy (OVT) aims to disrupt the tumor microenvironment and provide a unique therapeutic approach against solid tumors. Herpes simplex virus type-1 (HSV-1) has shown strong promise for treating various solid tumors and has been approved to treat melanoma and glioma in human patients. Previously, we reported the generation of an engineered HSV-1 vaccine strain VC2, which has shown exceptional promise as an oncolytic and immunotherapeutic virus. In the present work, we engineered VC2 to constitutively express the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) gene inserted in place of HSV-1 Glycoprotein C (gC). We tested the efficacy of VC2-GMCSF for its ability to generate antitumor response in the 4T1 stage four metastatic breast cancer mouse model. GM-CSF expression enhanced VC2 viral replication and infectious virus production. Tumors formed after 7 days of engraftment in the mammary fat pad of Balb/CJ mice were treated by injecting ~5 × 104 plaque forming units (PFU) of VC2/VC2-GMCSF once. Intratumor treatment did not appreciably reduce average primary tumor sizes. However, metastatic foci were significantly reduced in mice lungs treated with VC2-GMCSF compared to VC2 or mock treatment. VC2-GMCSF intratumoral treatment induced a stronger intratumor T cell infiltration but not an increased cytotoxic activity. A significant T cell infiltration was observed in the metastatic areas in VC2-GMCSF treated animals, which was associated with reduced pro-tumor marker PDL1 and VEGF gene expression. These results show that constitutive expression of GM-CSF enhanced the overall efficacy of VC2 for OVT. VC2-GMCSF holds promise as oncolytic and immunotherapeutic virotherapy for breast and other cancers.
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Affiliation(s)
- Rafiq Nabi
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Vladimir N Chouljenko
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Farhana Musarrat
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Megan E Davis
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Harikrishnan Mohan
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Reza Ghavimi
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Brent Stanfield
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Ojasvi Dutta
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
| | - Konstantin G Kousoulas
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA
- Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Baton Rouge, Louisiana, USA
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5
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Ray A, Hu KH, Kersten K, Courau T, Kuhn NF, Zaleta-Linares I, Samad B, Combes AJ, Krummel MF. Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis. J Exp Med 2025; 222:e20240957. [PMID: 39601781 PMCID: PMC11602655 DOI: 10.1084/jem.20240957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 09/01/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024] Open
Abstract
CD206 is a common marker of a putative immunosuppressive "M2" state in tumor-associated macrophages (TAMs). We made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ TAMs. Early depletion of CD206+ macrophages and monocytes (Mono/Macs) led to the indirect loss of conventional type I dendritic cells (cDC1), CD8 T cells, and NK cells in tumors. CD206+ TAMs robustly expressed CXCL9, contrasting with stress-responsive Spp1-expressing TAMs and immature monocytes, which became prominent with early depletion. CD206+ TAMs differentially attracted activated CD8 T cells, and the NK and CD8 T cells in CD206-depleted tumors were deficient in Cxcr3 and cDC1-supportive Xcl1 and Flt3l expressions. Disrupting this key antitumor axis decreased tumor control by antigen-specific T cells in mice. In human cancers, a CD206Replete, but not a CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, cDC1, and NK signatures and was associated with better survival. These findings negate the unqualified classification of CD206+ "M2-like" macrophages as immunosuppressive.
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MESH Headings
- Animals
- CD8-Positive T-Lymphocytes/immunology
- Mice
- Killer Cells, Natural/immunology
- Lectins, C-Type/metabolism
- Lectins, C-Type/genetics
- Receptors, Cell Surface/metabolism
- Receptors, Cell Surface/genetics
- Macrophages/immunology
- Macrophages/metabolism
- Humans
- Dendritic Cells/immunology
- Dendritic Cells/metabolism
- Mannose Receptor
- Mice, Inbred C57BL
- Mannose-Binding Lectins/metabolism
- Receptors, CXCR3/metabolism
- Receptors, CXCR3/genetics
- Chemokine CXCL9/metabolism
- Chemokine CXCL9/genetics
- Tumor-Associated Macrophages/immunology
- Tumor-Associated Macrophages/metabolism
- Membrane Glycoproteins/metabolism
- Membrane Glycoproteins/genetics
- Neoplasms/immunology
- Neoplasms/genetics
- Gene Knock-In Techniques
- Receptors, Immunologic/metabolism
- Receptors, Immunologic/genetics
- Monocytes/immunology
- Monocytes/metabolism
- Receptors, Chemokine
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Affiliation(s)
- Arja Ray
- Department of Pathology, University of California, San Francisco, CA, USA
- ImmunoX Initiative, University of California, San Francisco, CA, USA
| | - Kenneth H. Hu
- Department of Pathology, University of California, San Francisco, CA, USA
- ImmunoX Initiative, University of California, San Francisco, CA, USA
| | - Kelly Kersten
- Department of Pathology, University of California, San Francisco, CA, USA
- ImmunoX Initiative, University of California, San Francisco, CA, USA
| | - Tristan Courau
- Department of Pathology, University of California, San Francisco, CA, USA
- ImmunoX Initiative, University of California, San Francisco, CA, USA
| | - Nicholas F. Kuhn
- Department of Pathology, University of California, San Francisco, CA, USA
- ImmunoX Initiative, University of California, San Francisco, CA, USA
| | - Itzia Zaleta-Linares
- Department of Pathology, University of California, San Francisco, CA, USA
- ImmunoX Initiative, University of California, San Francisco, CA, USA
| | - Bushra Samad
- ImmunoX Initiative, University of California, San Francisco, CA, USA
- UCSF CoLabs, University of California, San Francisco, CA, USA
| | - Alexis J. Combes
- Department of Pathology, University of California, San Francisco, CA, USA
- ImmunoX Initiative, University of California, San Francisco, CA, USA
- UCSF CoLabs, University of California, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Matthew F. Krummel
- Department of Pathology, University of California, San Francisco, CA, USA
- ImmunoX Initiative, University of California, San Francisco, CA, USA
- UCSF CoLabs, University of California, San Francisco, CA, USA
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Crosson T, Bhat S, Wang JC, Salaun C, Fontaine E, Roversi K, Herzog H, Rafei M, Blunck R, Talbot S. Cytokines reprogram airway sensory neurons in asthma. Cell Rep 2024; 43:115045. [PMID: 39661516 DOI: 10.1016/j.celrep.2024.115045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 10/01/2024] [Accepted: 11/18/2024] [Indexed: 12/13/2024] Open
Abstract
Nociceptor neurons play a crucial role in maintaining the body's homeostasis by detecting and responding to potential environmental dangers. However, this function can be detrimental during allergic reactions, as vagal nociceptors contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we investigate the changes in the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identify a specific class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. In the ovalbumin mouse model of allergic airway inflammation, these neurons undergo significant reprogramming characterized by the upregulation of the neuropeptide Y (NPY) receptor Npy1r. A screening of cytokines and neurotrophins reveals that interleukin 1β (IL-1β), IL-13, and brain-derived neurotrophic factor (BDNF) drive part of this reprogramming. IL-13 triggers Npy1r overexpression in nociceptors via the JAK/STAT6 pathway. In parallel, NPY is released into the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. Single-cell RNA sequencing of lung immune cells reveals that a cell-specific knockout of NPY1R in nociceptor neurons in asthmatic mice altered T cell infiltration. Opposite findings are observed in asthmatic mice in which nociceptor neurons are chemically ablated. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, while a compensatory mechanism involving NPY1R limits the activity of nociceptor neurons.
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Affiliation(s)
- Theo Crosson
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Shreyas Bhat
- Centre Interdisciplinaire sur le Cerveau et l'Apprentissage, Université de Montréal, Montreal, QC, Canada; Département de Physique, Université de Montréal, Montreal, QC, Canada
| | - Jo-Chiao Wang
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Clara Salaun
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Eleanne Fontaine
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Katiane Roversi
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Herbert Herzog
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Moutih Rafei
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Rikard Blunck
- Centre Interdisciplinaire sur le Cerveau et l'Apprentissage, Université de Montréal, Montreal, QC, Canada; Département de Physique, Université de Montréal, Montreal, QC, Canada
| | - Sebastien Talbot
- Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
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7
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Vázquez Marrero VR, Dresler M, Haggadone MD, Lu A, Shin S. GM-CSF engages multiple signaling pathways to enhance pro-inflammatory cytokine responses in human monocytes during Legionella infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.05.627084. [PMID: 39713445 PMCID: PMC11661061 DOI: 10.1101/2024.12.05.627084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
The proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for host defense against a wide range of pathogens. We previously found that GM-CSF enhances inflammatory cytokine production in murine monocytes and is required for in vivo control of the intracellular bacterial pathogen Legionella pneumophila . It is unclear whether GM-CSF similarly augments cytokine production in human monocytes during bacterial infection. Here, we find that GM-CSF enhances inflammatory cytokine expression in Legionella- infected human monocytes by engaging multiple signaling pathways. Legionella - and TLR-dependent NF-𝜅B signaling is a prerequisite signal for GM-CSF to promote cytokine expression. Then, GM-CSF-driven JAK2/STAT5 signaling is required to augment cytokine expression in Legionella -infected human monocytes. We also found a role for PI-3K/Akt/mTORC1 signaling in GM-CSF-dependent upregulation of cytokine expression. Finally, glycolysis and amino acid metabolism are also critical for GM-CSF to boost cytokine gene expression in human monocytes during infection. Our findings show that GM-CSF-mediated enhancement of cytokine expression in infected human monocytes is regulated by multiple signaling pathways, thereby allowing the host to fine tune antibacterial immunity.
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8
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Toma AI, Shah D, Roth D, Piña JO, Hymel L, Turner T, Kamalakar A, Liu K, Bartsch P, Jacobs L, D'Souza R, Liotta D, Botchwey E, Willett NJ, Goudy SL. Accelerating Oral Wound Healing Using Bilayer Biomaterial Delivery of FTY720 Immunotherapy. Adv Healthc Mater 2024; 13:e2401480. [PMID: 39388502 PMCID: PMC11616256 DOI: 10.1002/adhm.202401480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 09/27/2024] [Indexed: 10/12/2024]
Abstract
Orofacial clefts are the most common congenital craniofacial anomaly. Adverse healing following cleft palate repair can lead to oronasal fistula (ONF), a persistent connection between the oral and nasal cavities. Although human allograft tissues are currently the gold standard for ONF repair, these methods carry risks of infection and rejection, often requiring surgical revision. Immunoregenerative therapies present a novel alternative approach to harness the body's immune response and enhance the wound healing environment. An FDA-approved immunomodulatory drug, FTY720, is repurposed to reduce lymphocyte egress and induce immune cell fate switching toward pro-regenerative phenotypes. In this study, a bilayer biomaterial system is engineered using Tegaderm to secure and control the delivery of FTY720-nanofiber scaffolds (FTY720-NF). The release kinetics of the bilayer FTY720-NF is optimized to maintain drug release for up to 7 days, ensuring safe transdermal absorption and tissue biodistribution. The comprehensive immunophenotyping results demonstrate a regenerative state transition in hybrid immune cells recruited to the wound site. Further, histological evaluations reveal a significant ONF closure in mice by day 7 following bilayer FTY720-NF implantation. These findings demonstrate the utility of immunomodulatory strategies for oral wound healing, better positing the field to develop more efficacious treatment options in pediatric patients.
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Affiliation(s)
- Afra I. Toma
- Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of TechnologyEmory UniversityAtlantaGA30322USA
- Department of Pediatrics and OtolaryngologyChildren's Healthcare of AtlantaAtlantaGA30329USA
| | - Daniel Shah
- Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of TechnologyEmory UniversityAtlantaGA30322USA
| | - Daniela Roth
- Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMD20892USA
| | - Jeremie Oliver Piña
- Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMD20892USA
| | - Lauren Hymel
- Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of TechnologyEmory UniversityAtlantaGA30322USA
| | - Thomas Turner
- Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of TechnologyEmory UniversityAtlantaGA30322USA
| | - Archana Kamalakar
- Department of Pediatrics and OtolaryngologyChildren's Healthcare of AtlantaAtlantaGA30329USA
| | - Ken Liu
- Department of ChemistryEmory UniversityAtlantaGA30322USA
| | - Perry Bartsch
- Department of ChemistryEmory UniversityAtlantaGA30322USA
| | - Leon Jacobs
- Department of ChemistryEmory UniversityAtlantaGA30322USA
| | - Rena D'Souza
- Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMD20892USA
| | - Dennis Liotta
- Department of ChemistryEmory UniversityAtlantaGA30322USA
| | - Edward Botchwey
- Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of TechnologyEmory UniversityAtlantaGA30322USA
| | - Nick J. Willett
- Phil and Penny Knight Campus for Accelerating Scientific ImpactUniversity of OregonEugeneOR97403USA
| | - Steven L. Goudy
- Wallace H. Coulter Department of Biomedical EngineeringGeorgia Institute of TechnologyEmory UniversityAtlantaGA30322USA
- Department of Pediatrics and OtolaryngologyChildren's Healthcare of AtlantaAtlantaGA30329USA
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9
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Debeuf N, Deckers J, Lameire S, Bosteels C, Hammad H, Lambrecht BN. Inhaled GM-CSF administered during ongoing pneumovirus infection alters myeloid and CD8 T cell immunity without affecting disease outcome. Front Immunol 2024; 15:1439789. [PMID: 39439800 PMCID: PMC11493702 DOI: 10.3389/fimmu.2024.1439789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024] Open
Abstract
Granulocyte-macrophage colony stimulating factor (GM-CSF) is a pleiotropic cytokine, able to promote both myelopoiesis and activation of immune cells. Particularly in the lung, GM-CSF plays an important homeostatic role in the development and maintenance of alveolar macrophages, and is therefore considered to play a role in respiratory virus infections such as influenza and SARS-CoV-2, although the benefits of GM-CSF treatment in clinical studies remain inconclusive. To address this, we tested inhaled GM-CSF treatment in the Pneumonia Virus of Mice (PVM) mouse model. Our findings show that local GM-CSF therapy during PVM disease increased local neutrophilia and monocyte-derived cell influx, but diminished CD8+ T cells responses. Despite this, the observed effects on T cells and myeloid cells did not result in an altered clinical outcome during PVM infection. We conclude that inhaled GM-CSF therapy cannot be considered as a universal protective therapy in respiratory virus infections.
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Affiliation(s)
- Nincy Debeuf
- Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Julie Deckers
- Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Sahine Lameire
- Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Cedric Bosteels
- Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Hamida Hammad
- Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Bart N. Lambrecht
- Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Department of Pulmonary Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
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10
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Beerepoot S, Wolf NI, van der Knaap MS, Nierkens S, Plantinga M. Heterozygous missense CSF1R variants hamper in vitro CD34+-derived dendritic cell generation but not in vivo dendritic cell development. Mol Immunol 2024; 174:41-46. [PMID: 39182279 DOI: 10.1016/j.molimm.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 08/14/2024] [Accepted: 08/15/2024] [Indexed: 08/27/2024]
Abstract
Colony stimulating factor 1 receptor (CSF1R) is an essential receptor for both colony stimulating factor 1 (CSF1) and interleukin (IL) 34 signaling expressed on monocyte precursors and myeloid cells, including monocytes, dendritic cells (DC), and microglia. In humans, dominant heterozygous pathogenic variants in CSF1R cause a neurological condition known as CSF1R-related disorder (CSF1R-RD), typically with late onset, previously referred to as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). CSF1R-RD is characterized by microglia reduction and altered monocyte function; however, the impact of pathogenic CSF1R variants on the human DC lineage remains largely unknown. We previously reported that cord blood CD34+ stem cell-derived DCs generated in vitro originate specifically from CSF1R expressing precursors. In this study, we examined the DC lineage of four unrelated patients with late-onset CSF1R-RD who carried heterozygous missense CSF1R variants (c.2330G>A, c.2375C>A, c.2329C>T, and c.2381T>C) affecting different amino acids in the protein tyrosine kinase domain of CSF1R. CD34+ stem cells and CD14+ monocytes were isolated from peripheral blood and subjected to an in vitro culture protocol to differentiate towards conventional DCs and monocyte-derived DCs, respectively. Flow cytometric analysis revealed that monocytes from patients with late-onset CSF1R-RD were still able to differentiate into monocyte-derived DCs in vitro, whereas the ability of CD34+ stem cells to differentiate into conventional DCs was impaired. Strikingly, the peripheral blood of patients contained all naturally occurring DC subsets. We conclude that the in vitro abrogation of DC-development in patients with heterozygous pathogenic missense CSF1R variants does not translate to an impairment in DC development in vivo and speculate that CSF1R signalling in vivo is compensated, which needs further study.
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Affiliation(s)
- Shanice Beerepoot
- Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, The Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Nicole I Wolf
- Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Marjo S van der Knaap
- Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, The Netherlands; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands
| | - Stefan Nierkens
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
| | - Maud Plantinga
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
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11
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Crosson T, Bhat S, Wang JC, Salaun C, Fontaine E, Roversi K, Herzog H, Rafei M, Blunck R, Talbot S. Cytokines reprogram airway sensory neurons in asthma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.01.26.525731. [PMID: 39345572 PMCID: PMC11429693 DOI: 10.1101/2023.01.26.525731] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Nociceptor neurons play a crucial role in maintaining the body's homeostasis by detecting and responding to potential dangers in the environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors can contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance, in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we aimed to investigate the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identified a unique class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. In the ovalbumin mouse model of airway inflammation, these neurons undergo significant reprogramming characterized by the upregulation of the NPY receptor Npy1r. A screening of cytokines and neurotrophins revealed that IL-1β, IL-13 and BDNF drive part of this reprogramming. IL-13 triggered Npy1r overexpression in nociceptors via the JAK/STAT6 pathway. In parallel, sympathetic neurons and macrophages release NPY in the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. Single-cell RNA sequencing of lung immune cells has revealed that a cell-specific knockout of Npy1r in nociceptor neurons in asthmatic mice leads to an increase in airway inflammation mediated by T cells. Opposite findings were observed in asthmatic mice in which nociceptor neurons were chemically ablated. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, while a compensatory mechanism involving NPY1R limits nociceptor neurons' activity.
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Affiliation(s)
- Théo Crosson
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | - Shreyas Bhat
- Centre Interdisciplinaire sur le Cerveau et l’Apprentissage, Université de Montréal, Canada
- Département de Physique, Université de Montréal, Canada
| | - Jo-Chiao Wang
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | - Clara Salaun
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | - Eleanne Fontaine
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | - Katiane Roversi
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | | | - Moutih Rafei
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | - Rikard Blunck
- Centre Interdisciplinaire sur le Cerveau et l’Apprentissage, Université de Montréal, Canada
- Département de Physique, Université de Montréal, Canada
| | - Sebastien Talbot
- Department of Physiology and Pharmacology, Karolinska Institutet. Sweden
- Department of Biomedical and Molecular Sciences, Queen’s University. Canada
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12
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Izquierdo JM. Novel insights into the sexual dimorphism-associated immune response. Cell Mol Immunol 2024; 21:804-806. [PMID: 38740923 PMCID: PMC11292011 DOI: 10.1038/s41423-024-01177-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/16/2024] Open
Affiliation(s)
- José M Izquierdo
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049, Madrid, Spain.
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13
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Hargitai R, Parráková L, Szatmári T, Monfort-Lanzas P, Galbiati V, Audouze K, Jornod F, Staal YCM, Burla S, Chary A, Gutleb AC, Lumniczky K, Vandebriel RJ, Gostner JM. Chemical respiratory sensitization-Current status of mechanistic understanding, knowledge gaps and possible identification methods of sensitizers. FRONTIERS IN TOXICOLOGY 2024; 6:1331803. [PMID: 39135743 PMCID: PMC11317441 DOI: 10.3389/ftox.2024.1331803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 05/27/2024] [Indexed: 08/15/2024] Open
Abstract
Respiratory sensitization is a complex immunological process eventually leading to hypersensitivity following re-exposure to the chemical. A frequent consequence is occupational asthma, which may occur after long latency periods. Although chemical-induced respiratory hypersensitivity has been known for decades, there are currently no comprehensive and validated approaches available for the prospective identification of chemicals that induce respiratory sensitization, while the expectations of new approach methodologies (NAMs) are high. A great hope is that due to a better understanding of the molecular key events, new methods can be developed now. However, this is a big challenge due to the different chemical classes to which respiratory sensitizers belong, as well as because of the complexity of the response and the late manifestation of symptoms. In this review article, the current information on respiratory sensitization related processes is summarized by introducing it in the available adverse outcome pathway (AOP) concept. Potentially useful models for prediction are discussed. Knowledge gaps and gaps of regulatory concern are identified.
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Affiliation(s)
- Rita Hargitai
- Unit of Radiation Medicine, Department of Radiobiology and Radiohygiene, National Centre for Public Health and Pharmacy (NCPHP), Budapest, Hungary
| | - Lucia Parráková
- Biochemical Immunotoxicology Group, Institute of Medical Biochemistry, Medical University of Innsbruck (MUI), Innsbruck, Austria
| | - Tünde Szatmári
- Unit of Radiation Medicine, Department of Radiobiology and Radiohygiene, National Centre for Public Health and Pharmacy (NCPHP), Budapest, Hungary
| | - Pablo Monfort-Lanzas
- Biochemical Immunotoxicology Group, Institute of Medical Biochemistry, Medical University of Innsbruck (MUI), Innsbruck, Austria
- Institute of Bioinformatics, Medical University of Innsbruck (MUI), Innsbruck, Austria
| | - Valentina Galbiati
- Laboratory of Toxicology, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università Degli Studi di Milano (UNIMI), Milano, Italy
| | | | | | - Yvonne C. M. Staal
- Centre for Health Protection, National Institute of Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Sabina Burla
- Luxembourg Institute of Science and Technology (LIST), Belvaux, Luxembourg
| | - Aline Chary
- Luxembourg Institute of Science and Technology (LIST), Belvaux, Luxembourg
| | - Arno C. Gutleb
- Luxembourg Institute of Science and Technology (LIST), Belvaux, Luxembourg
| | - Katalin Lumniczky
- Unit of Radiation Medicine, Department of Radiobiology and Radiohygiene, National Centre for Public Health and Pharmacy (NCPHP), Budapest, Hungary
| | - Rob J. Vandebriel
- Centre for Health Protection, National Institute of Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Johanna M. Gostner
- Biochemical Immunotoxicology Group, Institute of Medical Biochemistry, Medical University of Innsbruck (MUI), Innsbruck, Austria
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14
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Oliveira TY, Merkenschlager J, Eisenreich T, Bortolatto J, Yao KH, Gatti DM, Churchill GA, Nussenzweig MC, Breton G. Quantitative trait loci mapping provides insights into the genetic regulation of dendritic cell numbers in mouse tissues. Cell Rep 2024; 43:114296. [PMID: 38823019 PMCID: PMC11726347 DOI: 10.1016/j.celrep.2024.114296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 04/02/2024] [Accepted: 05/14/2024] [Indexed: 06/03/2024] Open
Abstract
To explore the influence of genetics on homeostatic regulation of dendritic cell (DC) numbers, we present a screen of DCs and their progenitors in lymphoid and non-lymphoid tissues in Collaborative Cross (CC) and Diversity Outbred (DO) mice. We report 30 and 71 loci with logarithm of the odds (LOD) scores >8.18 and ranging from 6.67 to 8.19, respectively. The analysis reveals the highly polygenic and pleiotropic architecture of this complex trait, including many of the previously identified genetic regulators of DC development and maturation. Two SNPs in genes potentially underlying variation in DC homeostasis, a splice variant in Gramd4 (rs235532740) and a missense variant in Orai3 (rs216659754), are confirmed by gene editing using CRISPR-Cas9. Gramd4 is a central regulator of DC homeostasis that impacts the entire DC lineage, and Orai3 regulates cDC2 numbers in tissues. Overall, the data reveal a large number of candidate genes regulating DC homeostasis in vivo.
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Affiliation(s)
- Thiago Y Oliveira
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Julia Merkenschlager
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Thomas Eisenreich
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Juliana Bortolatto
- Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY 10065, USA
| | - Kai-Hui Yao
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | | | | | - Michel C Nussenzweig
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute (HHMI), The Rockefeller University, New York, NY 10065, USA.
| | - Gaëlle Breton
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
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15
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Ray A, Hu KH, Kersten K, Courau T, Kuhn NF, Zaleta-Linares I, Samad B, Combes AJ, Krummel MF. Critical role of CD206+ macrophages in promoting a cDC1-NK-CD8 T cell anti-tumor immune axis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.10.31.560822. [PMID: 37961697 PMCID: PMC10635006 DOI: 10.1101/2023.10.31.560822] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Tumor-associated macrophages (TAMs) are frequently categorized as being 'M1' or 'M2' polarized, even as substantial data challenges this binary modeling of macrophage cell state. One molecule consistently referenced as a delineator of a putative immunosuppressive 'M2' state is the surface protein CD206. We thus made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ 'M2-like' TAMs and assess their correspondence with pro-tumoral immunity. Early, but not late depletion of CD206+ macrophages and monocytes (here, 'Mono/Macs') led to an indirect loss of a key anti-tumor network of NK cells, conventional type I dendritic cells (cDC1) and CD8 T cells. Among myeloid cells, we found that the CD206+ TAMs are the primary producers of CXCL9, and able to differentially attract activated CD8 T cells. In contrast, a population of stress-responsive TAMs ("Hypoxic" or Spp1+) and immature monocytes, which lack CD206 expression and become prominent following early depletion, expressed markedly diminished levels of CXCL9. Those NK and CD8 T cells which enter CD206-depleted tumors express vastly reduced levels of the corresponding receptor Cxcr3, the cDC1-attracting chemokine Xcl1 and cDC1 growth factor Flt3l transcripts. Consistent with the loss of this critical network, early CD206+ TAM depletion decreased tumor control by antigen specific CD8 T cells in mice. Likewise, in humans, the CD206Replete, but not the CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, NK cell and stimulatory cDC1 gene signatures and transcriptomic signatures skewed towards CD206Replete Mono/Macs associated with better survival. Together, these findings negate the unqualified classification of CD206+ 'M2-like' macrophages as immunosuppressive by illuminating contexts for their role in organizing a critical tumor-reactive archetype of immunity.
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Affiliation(s)
- Arja Ray
- Department of Pathology, University of California, San Francisco, CA 94143, USA
- ImmunoX Initiative, University of California, San Francisco, CA 94143, USA
| | - Kenneth H. Hu
- Department of Pathology, University of California, San Francisco, CA 94143, USA
- ImmunoX Initiative, University of California, San Francisco, CA 94143, USA
| | - Kelly Kersten
- Department of Pathology, University of California, San Francisco, CA 94143, USA
- ImmunoX Initiative, University of California, San Francisco, CA 94143, USA
| | - Tristan Courau
- Department of Pathology, University of California, San Francisco, CA 94143, USA
- ImmunoX Initiative, University of California, San Francisco, CA 94143, USA
| | - Nicholas F. Kuhn
- Department of Pathology, University of California, San Francisco, CA 94143, USA
- ImmunoX Initiative, University of California, San Francisco, CA 94143, USA
| | - Itzia Zaleta-Linares
- Department of Pathology, University of California, San Francisco, CA 94143, USA
- ImmunoX Initiative, University of California, San Francisco, CA 94143, USA
| | - Bushra Samad
- ImmunoX Initiative, University of California, San Francisco, CA 94143, USA
- UCSF CoLabs, University of California, San Francisco, CA 94143, USA
| | - Alexis J. Combes
- Department of Pathology, University of California, San Francisco, CA 94143, USA
- ImmunoX Initiative, University of California, San Francisco, CA 94143, USA
- UCSF CoLabs, University of California, San Francisco, CA 94143, USA
- Department of Medicine, University of California, San Francisco, CA 94143, USA
| | - Matthew F. Krummel
- Department of Pathology, University of California, San Francisco, CA 94143, USA
- ImmunoX Initiative, University of California, San Francisco, CA 94143, USA
- UCSF CoLabs, University of California, San Francisco, CA 94143, USA
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16
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Wilkinson CL, Nakano K, Grimm SA, Whitehead GS, Arao Y, Blackshear PJ, Karmaus PW, Fessler MB, Cook DN, Nakano H. GM-CSF-dependent CD301b+ lung dendritic cells confer tolerance to inhaled allergens. RESEARCH SQUARE 2024:rs.3.rs-4414130. [PMID: 38883724 PMCID: PMC11177951 DOI: 10.21203/rs.3.rs-4414130/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
The severity of allergic asthma is driven by the balance between allergen-specific T regulatory (Treg) and T helper (Th)2 cells. However, it is unclear whether specific subsets of conventional dendritic cells (cDCs) promote the differentiation of these two T cell lineaeges. We have identified a subset of lung resident type 2 cDCs (cDC2s) that display high levels of CD301b and have potent Treg-inducing activity ex vivo. Single cell RNA sequencing and adoptive transfer experiments show that during allergic sensitization, many CD301b+ cDC2s transition in a stepwise manner to CD200+ cDC2s that selectively promote Th2 differentiation. GM-CSF augments the development and maintenance of CD301b+ cDC2s in vivo, and also selectively expands Treg-inducing CD301b+ cDC2s derived from bone marrow. Upon their adoptive transfer to recipient mice, lung-derived CD301b+ cDC2s confer immunological tolerance to inhaled allergens. Thus, GM-CSF maintains lung homeostasis by increasing numbers of Treg-inducing CD301b+ cDC2s.
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Affiliation(s)
- Christina L. Wilkinson
- Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
| | - Keiko Nakano
- Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
| | - Sara A. Grimm
- Integrative Bioinformatics Support Group, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
| | - Gregory S. Whitehead
- Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
| | - Yukitomo Arao
- Signal Transduction Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
| | - Perry J. Blackshear
- Signal Transduction Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
| | - Peer W. Karmaus
- Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
| | - Michael B. Fessler
- Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
| | - Donald N. Cook
- Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
| | - Hideki Nakano
- Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA
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17
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Sohrabi S, Masoumi J, Naseri B, Ghorbaninezhad F, Alipour S, Kazemi T, Ahmadian Heris J, Aghebati Maleki L, Basirjafar P, Zandvakili R, Doustvandi MA, Baradaran B. STATs signaling pathways in dendritic cells: As potential therapeutic targets? Int Rev Immunol 2024; 43:138-159. [PMID: 37886903 DOI: 10.1080/08830185.2023.2274576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/17/2023] [Accepted: 10/16/2023] [Indexed: 10/28/2023]
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells (APCs), including heterogenous populations with phenotypic and functional diversity that coordinate bridging innate and adaptive immunity. Signal transducer and activator of transcriptions (STAT) factors as key proteins in cytokine signaling were shown to play distinct roles in the maturation and antigen presentation of DCs and play a pivotal role in modulating immune responses mediated by DCs such as differentiation of T cells to T helper (Th) 1, Th2 or regulatory T (Treg) cells. This review sheds light on the importance of STAT transcription factors' signaling pathways in different subtypes of DCs and highlights their targeting potential usages for improving DC-based immunotherapies for patients who suffer from cancer or diverse autoimmune conditions according to the type of the STAT transcription factor and its specific activating or inhibitory agent.
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Affiliation(s)
- Sepideh Sohrabi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Masoumi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahar Naseri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Shiva Alipour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Pedram Basirjafar
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Raziyeh Zandvakili
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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18
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Chi L, Liu C, Gribonika I, Gschwend J, Corral D, Han SJ, Lim AI, Rivera CA, Link VM, Wells AC, Bouladoux N, Collins N, Lima-Junior DS, Enamorado M, Rehermann B, Laffont S, Guéry JC, Tussiwand R, Schneider C, Belkaid Y. Sexual dimorphism in skin immunity is mediated by an androgen-ILC2-dendritic cell axis. Science 2024; 384:eadk6200. [PMID: 38574174 DOI: 10.1126/science.adk6200] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 02/26/2024] [Indexed: 04/06/2024]
Abstract
Males and females exhibit profound differences in immune responses and disease susceptibility. However, the factors responsible for sex differences in tissue immunity remain poorly understood. Here, we uncovered a dominant role for type 2 innate lymphoid cells (ILC2s) in shaping sexual immune dimorphism within the skin. Mechanistically, negative regulation of ILC2s by androgens leads to a reduction in dendritic cell accumulation and activation in males, along with reduced tissue immunity. Collectively, our results reveal a role for the androgen-ILC2-dendritic cell axis in controlling sexual immune dimorphism. Moreover, this work proposes that tissue immune set points are defined by the dual action of sex hormones and the microbiota, with sex hormones controlling the strength of local immunity and microbiota calibrating its tone.
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Affiliation(s)
- Liang Chi
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Can Liu
- Multiscale Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Inta Gribonika
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Julia Gschwend
- Institute of Physiology, University of Zurich, CH-8057 Zürich, Switzerland
| | - Dan Corral
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Seong-Ji Han
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ai Ing Lim
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Claudia A Rivera
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Verena M Link
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Alexandria C Wells
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nicolas Bouladoux
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nicholas Collins
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Djalma S Lima-Junior
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Michel Enamorado
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sophie Laffont
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291, CNRS UMR5051, University Toulouse III, Toulouse, France
| | - Jean-Charles Guéry
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291, CNRS UMR5051, University Toulouse III, Toulouse, France
| | - Roxane Tussiwand
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
| | | | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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19
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Chen Y, Zhou M, Liu J, Chi J, Yang X, Du Q, Ren X, Tian K. Multiple effects of dose-related GM-CSF on periodontal resorption in deep-frozen grafted teeth: A reverse study. Int Immunopharmacol 2024; 130:111745. [PMID: 38430803 DOI: 10.1016/j.intimp.2024.111745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 02/09/2024] [Accepted: 02/20/2024] [Indexed: 03/05/2024]
Abstract
Autologous tooth grafting is a dental restorative modality based on periodontal ligament healing.Human periodontal ligament stem cells(PDLSCs) are involved in the formation and remodeling of periodontal tissue.Based on previous findings, the proliferation and differentiation of processing cryopreserved periodontal ligament stem cells (PDLSCs) exhibit similarities to those of fresh cells. However, there is evident absorption in the transplanted frozen tooth's roots and bones, with the underlying cause remaining unknown. Granulocyte macrophage colony-stimulating factor(GM-CSF) is named for its produce granulocyte and macrophage precursors from bone marrow precursors, and it also serves as one of the regulatory factors in inflammatory and osteoclast formation. This study aimed to investigate changes in GM-CSF expression in frozen PDLSCs (fhPDLSCs) and evaluate the impact of GM-CSF on PDLSCs with respect to cellular activity and osteogenic ability. The role of GM-CSF in periodontal absorption was further speculated by comparing with IL-1β. The results revealed a significant increase in GM-CSF levels from fhPDLSCs compared to fresh cells, which exhibited an equivalent inflammatory stimulation effect as 1 ng/ml IL-1β. Cell viability also increased with increasing concentrations of GM-CSF; however, the GM-CSF from fhPDLSCs was not sufficient to significantly trigger osteoclastic factors. Considering its interaction with IL-1β and positive feedback mechanism, environments with high doses of GM-CSF derived from fhPDLSCs are more likely to activate osteoclastic responses.Therefore, for frozen tooth replantation, great attention should be paid to anti-inflammation and anti-infection.GM-CSF may serve as a potential therapeutic target for inhibiting periodontal resorption in delayed grafts.
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Affiliation(s)
- Yue Chen
- Department of Stomatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Min Zhou
- Department of Stomatology, Chengfei Hospital, Chengdu 610091, China
| | - Juanxiu Liu
- Department of Stomatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Junzhou Chi
- Department of Stomatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Xin Yang
- Department of Stomatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Qin Du
- Department of Stomatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Xiaohua Ren
- Department of Stomatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China.
| | - Kun Tian
- Department of Stomatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China.
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20
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Voissière A, Gomez-Roca C, Chabaud S, Rodriguez C, Nkodia A, Berthet J, Montane L, Bidaux AS, Treilleux I, Eberst L, Terret C, Korakis I, Garin G, Pérol D, Delord JP, Caux C, Dubois B, Ménétrier-Caux C, Bendriss-Vermare N, Cassier PA. The CSF-1R inhibitor pexidartinib affects FLT3-dependent DC differentiation and may antagonize durvalumab effect in patients with advanced cancers. Sci Transl Med 2024; 16:eadd1834. [PMID: 38266104 DOI: 10.1126/scitranslmed.add1834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 12/21/2023] [Indexed: 01/26/2024]
Abstract
Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R-directed tyrosine kinase inhibitor (TKI), and durvalumab (anti-PD-L1) in patients with advanced colorectal and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1-dependent suppressive TAM. Forty-seven patients were enrolled. No unexpected toxicities were observed, one (2%) high microsatellite instability CRC patient had a partial response, and seven (15%) patients experienced stable disease as their best response. Increase of CSF-1 concentrations and decrease of CD14lowCD16high monocytes in peripheral blood mononuclear cells (PBMCs) confirmed CSF-1R engagement. Treatment decreased blood dendritic cell (DC) subsets and impaired IFN-λ/IL-29 production by type 1 conventional DCs in ex vivo TLR3-stimulated PBMCs. Pexidartinib also targets c-KIT and FLT3, both key growth factor receptors of DC development and maturation. In patients, FLT3-L concentrations increased with pexidartinib treatment, and AKT phosphorylation induced by FLT3-L ex vivo stimulation was abrogated by pexidartinib in human blood DC subsets. In addition, pexidartinib impaired the FLT3-L- but not GM-CSF-dependent generation of DC subsets from murine bone marrow (BM) progenitors in vitro and decreased DC frequency in BM and tumor-draining lymph node in vivo. Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has a deleterious effect on DC differentiation, which may explain the limited antitumor clinical activity observed in this study. This work suggests that inhibition of FLT3 should be considered when combining TKIs with immune checkpoint inhibitors.
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Affiliation(s)
- Aurélien Voissière
- Université Claude Bernard Lyon 1, INSERM U-1052, CNRS 5286, Cancer Research Center of Lyon, Lyon, France
| | - Carlos Gomez-Roca
- Department of Medical Oncology, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | - Sylvie Chabaud
- Clinical Research Platform (DRCI), Centre Léon Bérard, Lyon, France
| | - Céline Rodriguez
- Université Claude Bernard Lyon 1, INSERM U-1052, CNRS 5286, Cancer Research Center of Lyon, Lyon, France
- Lyon Immunotherapy for Cancer Laboratory (LICL), Centre Léon Bérard, Lyon, France
| | - Axelle Nkodia
- Lyon Immunotherapy for Cancer Laboratory (LICL), Centre Léon Bérard, Lyon, France
| | - Justine Berthet
- Université Claude Bernard Lyon 1, INSERM U-1052, CNRS 5286, Cancer Research Center of Lyon, Lyon, France
- Lyon Immunotherapy for Cancer Laboratory (LICL), Centre Léon Bérard, Lyon, France
| | - Laure Montane
- Clinical Research Platform (DRCI), Centre Léon Bérard, Lyon, France
| | | | | | - Lauriane Eberst
- Department of Medical Oncology, Centre Léon Bérard, 28 rue Laennec, Lyon, France
| | - Catherine Terret
- Department of Medical Oncology, Centre Léon Bérard, 28 rue Laennec, Lyon, France
| | - Iphigénie Korakis
- Department of Medical Oncology, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | - Gwenaelle Garin
- Clinical Research Platform (DRCI), Centre Léon Bérard, Lyon, France
| | - David Pérol
- Clinical Research Platform (DRCI), Centre Léon Bérard, Lyon, France
| | - Jean-Pierre Delord
- Department of Medical Oncology, Institut Claudius Regaud/Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | - Christophe Caux
- Université Claude Bernard Lyon 1, INSERM U-1052, CNRS 5286, Cancer Research Center of Lyon, Lyon, France
- Lyon Immunotherapy for Cancer Laboratory (LICL), Centre Léon Bérard, Lyon, France
| | - Bertrand Dubois
- Université Claude Bernard Lyon 1, INSERM U-1052, CNRS 5286, Cancer Research Center of Lyon, Lyon, France
- Lyon Immunotherapy for Cancer Laboratory (LICL), Centre Léon Bérard, Lyon, France
| | - Christine Ménétrier-Caux
- Université Claude Bernard Lyon 1, INSERM U-1052, CNRS 5286, Cancer Research Center of Lyon, Lyon, France
- Lyon Immunotherapy for Cancer Laboratory (LICL), Centre Léon Bérard, Lyon, France
| | - Nathalie Bendriss-Vermare
- Université Claude Bernard Lyon 1, INSERM U-1052, CNRS 5286, Cancer Research Center of Lyon, Lyon, France
- Lyon Immunotherapy for Cancer Laboratory (LICL), Centre Léon Bérard, Lyon, France
| | - Philippe A Cassier
- Department of Medical Oncology, Centre Léon Bérard, 28 rue Laennec, Lyon, France
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21
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Mahajan D, Kumar T, Rath PK, Sahoo AK, Mishra BP, Kumar S, Nayak NR, Jena MK. Dendritic Cells and the Establishment of Fetomaternal Tolerance for Successful Human Pregnancy. Arch Immunol Ther Exp (Warsz) 2024; 72:aite-2024-0010. [PMID: 38782369 DOI: 10.2478/aite-2024-0010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 02/26/2024] [Indexed: 05/25/2024]
Abstract
Pregnancy is a remarkable event where the semi-allogeneic fetus develops in the mother's uterus, despite genetic and immunological differences. The antigen handling and processing at the maternal-fetal interface during pregnancy appear to be crucial for the adaptation of the maternal immune system and for tolerance to the developing fetus and placenta. Maternal antigen-presenting cells (APCs), such as macrophages (Mφs) and dendritic cells (DCs), are present at the maternal-fetal interface throughout pregnancy and are believed to play a crucial role in this process. Despite numerous studies focusing on the significance of Mφs, there is limited knowledge regarding the contribution of DCs in fetomaternal tolerance during pregnancy, making it a relatively new and growing field of research. This review focuses on how the behavior of DCs at the maternal-fetal interface adapts to pregnancy's unique demands. Moreover, it discusses how DCs interact with other cells in the decidual leukocyte network to regulate uterine and placental homeostasis and the local maternal immune responses to the fetus. The review particularly examines the different cell lineages of DCs with specific surface markers, which have not been critically reviewed in previous publications. Additionally, it emphasizes the impact that even minor disruptions in DC functions can have on pregnancy-related complications and proposes further research into the potential therapeutic benefits of targeting DCs to manage these complications.
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Affiliation(s)
- Deviyani Mahajan
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Tarun Kumar
- Department of Veterinary Clinical Complex, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana 125001, India
| | - Prasana Kumar Rath
- Department of Veterinary Pathology, College of Veterinary Science and AH, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha 751003, India
| | - Anjan Kumar Sahoo
- Department of Veterinary Pathology, College of Veterinary Science and AH, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha 751003, India
- Department of Veterinary Surgery and Radiology, College of Veterinary Science and AH, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha 751003, India
| | - Bidyut Prava Mishra
- Department of Veterinary Pathology, College of Veterinary Science and AH, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha 751003, India
- Department of Livestock Products Technology, College of Veterinary Science and AH, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha 751003, India
| | - Sudarshan Kumar
- Proteomics and Structural Biology Laboratory, Animal Biotechnology Centre, National Dairy Research Institute, Karnal, Haryana 132001, India
| | - Nihar Ranjan Nayak
- Department of Obstetrics and Gynecology, UMKC School of Medicine, Kansas City, MO 64108, USA
| | - Manoj Kumar Jena
- Department of Biotechnology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab 144411, India
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22
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Toma AI, Shah D, Roth D, Oliver Piña J, Hymel L, Turner T, Kamalakar A, Liu K, Bartsch P, Jacobs L, D'Souza R, Liotta D, Botchwey E, Willett NJ, Goudy SL. Harnessing Bilayer Biomaterial Delivery of FTY720 as an Immunotherapy to Accelerate Oral Wound Healing. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.22.573096. [PMID: 38187740 PMCID: PMC10769397 DOI: 10.1101/2023.12.22.573096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Orofacial clefts are the most common craniofacial congenital anomaly. Following cleft palate repair, up to 60% of surgeries have wound healing complications leading to oronasal fistula (ONF), a persistent connection between the roof of the mouth and the nasal cavity. The current gold standard methods for ONF repair use human allograft tissues; however, these procedures have risks of graft infection and/or rejection, requiring surgical revisions. Immunoregenerative therapies present a novel alternative approach to harness the body's immune response and enhance the wound healing environment. We utilized a repurposed FDA-approved immunomodulatory drug, FTY720, to reduce the egress of lymphocytes and induce immune cell fate switching toward pro-regenerative phenotypes. Here, we engineered a bilayer biomaterial system using Tegaderm™, a liquid-impermeable wound dressing, to secure and control the delivery of FTY720- nanofiber scaffolds (FTY720-NF). We optimized release kinetics of the bilayer FTY720-NF to sustain drug release for up to 7d with safe, efficacious transdermal absorption and tissue biodistribution. Through comprehensive immunophenotyping, our results illustrate a pseudotime pro-regenerative state transition in recruited hybrid immune cells to the wound site. Additional histological assessments established a significant difference in full thickness ONF closure in mice on Day 7 following treatment with bilayer FTY720-NF, compared to controls. These findings demonstrate the utility of immunomodulatory strategies for oral wound healing, better positing the field to develop more efficacious treatment options for pediatric patients. One Sentence Summary Local delivery of bilayer FTY720-nanofiber scaffolds in an ONF mouse model promotes complete wound closure through modulation of pro-regenerative immune and stromal cells.
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23
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Yu X, Zhang Y, Hou L, Qiao X, Zhang Y, Cheng H, Lu H, Chen J, Du L, Zheng Q, Hou J, Tong G. Increases in Cellular Immune Responses Due to Positive Effect of CVC1302-Induced Lysosomal Escape in Mice. Vaccines (Basel) 2023; 11:1718. [PMID: 38006050 PMCID: PMC10675172 DOI: 10.3390/vaccines11111718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/08/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
This study found a higher percentage of CD8+ T cells in piglets immunized with a CVC1302-adjuvanted inactivated foot-and-mouth disease virus (FMDV) vaccine. We wondered whether the CVC1302-adjuvanted inactivated FMDV vaccine promoted cellular immunity by promoting the antigen cross-presentation efficiency of ovalbumin (OVA) through dendritic cells (DCs), mainly via cytosolic pathways. This was demonstrated by the enhanced levels of lysosomal escape of OVA in the DCs loaded with OVA and CVC1302. The higher levels of ROS and significantly enhanced elevated lysosomal pH levels in the DCs facilitated the lysosomal escape of OVA. Significantly enhanced CTL activity levels was observed in the mice immunized with OVA-CVC1302. Overall, CVC1302 increased the cross-presentation of exogenous antigens and the cross-priming of CD8+ T cells by alkalizing the lysosomal pH and facilitating the lysosomal escape of antigens. These studies shed new light on the development of immunopotentiators to improve cellular immunity induced by vaccines.
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Affiliation(s)
- Xiaoming Yu
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Yuanyuan Zhang
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Liting Hou
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Xuwen Qiao
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Yuanpeng Zhang
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Haiwei Cheng
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Haiyan Lu
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Jin Chen
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Luping Du
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Qisheng Zheng
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Jibo Hou
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
- Jiangsu Key Laboratory for Food Quality and Safety—State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing 210014, China
- Guo Tai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou 225300, China
| | - Guangzhi Tong
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China
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24
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Pittet MJ, Di Pilato M, Garris C, Mempel TR. Dendritic cells as shepherds of T cell immunity in cancer. Immunity 2023; 56:2218-2230. [PMID: 37708889 PMCID: PMC10591862 DOI: 10.1016/j.immuni.2023.08.014] [Citation(s) in RCA: 83] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 08/03/2023] [Accepted: 08/17/2023] [Indexed: 09/16/2023]
Abstract
In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses. Here, we review the current understanding of DC-T cell interactions at both priming and effector sites of immune responses. We place emerging insights into DC functions in tumor immunity in the context of DC development, ontogeny, and functions in other settings and propose that DCs control at least two T cell-associated checkpoints of the cancer immunity cycle. Our understanding of both checkpoints has implications for the development of new approaches to cancer immunotherapy.
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Affiliation(s)
- Mikael J Pittet
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Ludwig Institute for Cancer Research, Lausanne, Switzerland; AGORA Cancer Center, Swiss Cancer Center Leman, Lausanne, Switzerland; Department of Oncology, Geneva University Hospitals (HUG), Geneva, Switzerland.
| | - Mauro Di Pilato
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Christopher Garris
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Thorsten R Mempel
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA 02115, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02129, USA.
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25
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Johnston LJ, Barningham L, Campbell EL, Cerovic V, Duckworth CA, Luu L, Wastling J, Derricott H, Coombes JL. A novel in vitro model of the small intestinal epithelium in co-culture with 'gut-like' dendritic cells. DISCOVERY IMMUNOLOGY 2023; 2:kyad018. [PMID: 38567056 PMCID: PMC10917230 DOI: 10.1093/discim/kyad018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/31/2023] [Accepted: 10/05/2023] [Indexed: 04/04/2024]
Abstract
Cross-talk between dendritic cells (DCs) and the intestinal epithelium is important in the decision to mount a protective immune response to a pathogen or to regulate potentially damaging responses to food antigens and the microbiota. Failures in this decision-making process contribute to the development of intestinal inflammation, making the molecular signals that pass between DCs and intestinal epithelial cells potential therapeutic targets. Until now, in vitro models with sufficient complexity to understand these interactions have been lacking. Here, we outline the development of a co-culture model of in vitro differentiated 'gut-like' DCs with small intestinal organoids (enteroids). Sequential exposure of murine bone marrow progenitors to Flt3L, granulocyte macrophage colony-stimulating factor (GM-CSF) and all-trans-retinoic acid (RA) resulted in the generation of a distinct population of conventional DCs expressing CD11b+SIRPα+CD103+/- (cDC2) exhibiting retinaldehyde dehydrogenase (RALDH) activity. These 'gut-like' DCs extended transepithelial dendrites across the intact epithelium of enteroids. 'Gut-like' DC in co-culture with enteroids can be utilized to define how epithelial cells and cDCs communicate in the intestine under a variety of different physiological conditions, including exposure to different nutrients, natural products, components of the microbiota, or pathogens. Surprisingly, we found that co-culture with enteroids resulted in a loss of RALDH activity in 'gut-like' DCs. Continued provision of GM-CSF and RA during co-culture was required to oppose putative negative signals from the enteroid epithelium. Our data contribute to a growing understanding of how intestinal cDCs assess environmental conditions to ensure appropriate activation of the immune response.
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Affiliation(s)
- Luke J Johnston
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK
| | - Liam Barningham
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Eric L Campbell
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK
| | - Vuk Cerovic
- Institute of Molecular Medicine, RWTH University Hospital, Aachen, Germany
| | - Carrie A Duckworth
- Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Lisa Luu
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Jonathan Wastling
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
- College of Health, Medicine and Life Sciences, Brunel University London, Kingston Lane, Uxbridge, Middlesex, UK
| | - Hayley Derricott
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Janine L Coombes
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
- School of Pharmacy and Life Sciences, Robert Gordon University, Aberdeen, UK
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Upadhaya P, Lamenza FF, Shrestha S, Roth P, Jagadeesha S, Pracha H, Horn NA, Oghumu S. Berry Extracts and Their Bioactive Compounds Mitigate LPS and DNFB-Mediated Dendritic Cell Activation and Induction of Antigen Specific T-Cell Effector Responses. Antioxidants (Basel) 2023; 12:1667. [PMID: 37759970 PMCID: PMC10525528 DOI: 10.3390/antiox12091667] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 08/08/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
Berries have gained widespread recognition for their abundant natural antioxidant, anti-inflammatory, and immunomodulatory properties. However, there has been limited research conducted thus far to investigate the role of the active constituents of berries in alleviating contact hypersensitivity (CHS), the most prevalent occupational dermatological disease. Our study involved an ex vivo investigation aimed at evaluating the impact of black raspberry extract (BRB-E) and various natural compounds found in berries, such as protocatechuic acid (PCA), proanthocyanidins (PANT), ellagic acid (EA), and kaempferol (KMP), on mitigating the pathogenicity of CHS. We examined the efficacy of these natural compounds on the activation of dendritic cells (DCs) triggered by 2,4-dinitrofluorobenzene (DNFB) and lipopolysaccharide (LPS). Specifically, we measured the expression of activation markers CD40, CD80, CD83, and CD86 and the production of proinflammatory cytokines, including Interleukin (IL)-12, IL-6, TNF-α, and IL-10, to gain further insights. Potential mechanisms through which these phytochemicals could alleviate CHS were also investigated by investigating the role of phospho-ERK. Subsequently, DCs were co-cultured with T-cells specific to the OVA323-339 peptide to examine the specific T-cell effector responses resulting from these interactions. Our findings demonstrated that BRB-E, PCA, PANT, and EA, but not KMP, inhibited phosphorylation of ERK in LPS-activated DCs. At higher doses, EA significantly reduced expression of all the activation markers studied in DNFB- and LPS-stimulated DCs. All compounds tested reduced the level of IL-6 in DNFB-stimulated DCs in Flt3L as well as in GM-CSF-derived DCs. However, levels of IL-12 were reduced by all the tested compounds in LPS-stimulated Flt3L-derived BMDCs. PCA, PANT, EA, and KMP inhibited the activated DC-mediated Interferon (IFN)-γ and IL-17 production by T-cells. Interestingly, PANT, EA, and KMP significantly reduced T-cell proliferation and the associated IL-2 production. Our study provides evidence for differential effects of berry extracts and natural compounds on DNFB and LPS-activated DCs revealing potential novel approaches for mitigating CHS.
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Affiliation(s)
- Puja Upadhaya
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (P.U.); (F.F.L.); (S.S.); (P.R.); (S.J.); (H.P.); (N.A.H.)
| | - Felipe F. Lamenza
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (P.U.); (F.F.L.); (S.S.); (P.R.); (S.J.); (H.P.); (N.A.H.)
- Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA
| | - Suvekshya Shrestha
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (P.U.); (F.F.L.); (S.S.); (P.R.); (S.J.); (H.P.); (N.A.H.)
- Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA
| | - Peyton Roth
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (P.U.); (F.F.L.); (S.S.); (P.R.); (S.J.); (H.P.); (N.A.H.)
| | - Sushmitha Jagadeesha
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (P.U.); (F.F.L.); (S.S.); (P.R.); (S.J.); (H.P.); (N.A.H.)
| | - Hasan Pracha
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (P.U.); (F.F.L.); (S.S.); (P.R.); (S.J.); (H.P.); (N.A.H.)
| | - Natalie A. Horn
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (P.U.); (F.F.L.); (S.S.); (P.R.); (S.J.); (H.P.); (N.A.H.)
| | - Steve Oghumu
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (P.U.); (F.F.L.); (S.S.); (P.R.); (S.J.); (H.P.); (N.A.H.)
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Chen Y, Li F, Hua M, Liang M, Song C. Role of GM-CSF in lung balance and disease. Front Immunol 2023; 14:1158859. [PMID: 37081870 PMCID: PMC10111008 DOI: 10.3389/fimmu.2023.1158859] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 03/24/2023] [Indexed: 04/07/2023] Open
Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor originally identified as a stimulus that induces the differentiation of bone marrow progenitor cells into granulocytes and macrophages. GM-CSF is now considered to be a multi-origin and pleiotropic cytokine. GM-CSF receptor signals activate JAK2 and induce nuclear signals through the JAK-STAT, MAPK, PI3K, and other pathways. In addition to promoting the metabolism of pulmonary surfactant and the maturation and differentiation of alveolar macrophages, GM-CSF plays a key role in interstitial lung disease, allergic lung disease, alcoholic lung disease, and pulmonary bacterial, fungal, and viral infections. This article reviews the latest knowledge on the relationship between GM-CSF and lung balance and lung disease, and indicates that there is much more to GM-CSF than its name suggests.
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Affiliation(s)
- Yingzi Chen
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Anhui, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Anhui, China
| | - Fan Li
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Anhui, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Anhui, China
| | - Mengqing Hua
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Anhui, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Anhui, China
| | - Meng Liang
- Department of Biotechnology, School of Life Science, Bengbu Medical College, Anhui, China
- *Correspondence: Chuanwang Song, ; Meng Liang,
| | - Chuanwang Song
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Anhui, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Anhui, China
- *Correspondence: Chuanwang Song, ; Meng Liang,
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Backer RA, Probst HC, Clausen BE. Classical DC2 subsets and monocyte-derived DC: Delineating the developmental and functional relationship. Eur J Immunol 2023; 53:e2149548. [PMID: 36642930 DOI: 10.1002/eji.202149548] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 11/08/2023] [Accepted: 01/13/2023] [Indexed: 01/17/2023]
Abstract
To specifically tailor immune responses to a given pathogenic threat, dendritic cells (DC) are highly heterogeneous and comprise many specialized subtypes, including conventional DC (cDC) and monocyte-derived DC (MoDC), each with distinct developmental and functional characteristics. However, the functional relationship between cDC and MoDC is not fully understood, as the overlapping phenotypes of certain type 2 cDC (cDC2) subsets and MoDC do not allow satisfactory distinction of these cells in the tissue, particularly during inflammation. However, precise cDC2 and MoDC classification is required for studies addressing how these diverse cell types control immune responses and is therefore currently one of the major interests in the field of cDC research. This review will revise murine cDC2 and MoDC biology in the steady state and under inflammatory conditions and discusses the commonalities and differences between ESAMlo cDC2, inflammatory cDC2, and MoDC and their relative contribution to the initiation, propagation, and regulation of immune responses.
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Affiliation(s)
- Ronald A Backer
- Institute for Molecular Medicine, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Hans Christian Probst
- Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Institute for Immunology, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Björn E Clausen
- Institute for Molecular Medicine, Paul Klein Center for Immune Intervention, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
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29
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Cui TX, Brady AE, Zhang YJ, Fulton CT, Goldsmith AM, Popova AP. Early-life hyperoxia-induced Flt3L drives neonatal lung dendritic cell expansion and proinflammatory responses. Front Immunol 2023; 14:1116675. [PMID: 36845082 PMCID: PMC9950736 DOI: 10.3389/fimmu.2023.1116675] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 01/26/2023] [Indexed: 02/12/2023] Open
Abstract
Premature infants with chronic lung disease, bronchopulmonary dysplasia (BPD), develop recurrent cough and wheezing following respiratory viral infections. The mechanisms driving the chronic respiratory symptoms are ill-defined. We have shown that hyperoxic exposure of neonatal mice (a model of BPD) increases the activated lung CD103+ dendritic cells (DCs) and these DCs are required for exaggerated proinflammatory responses to rhinovirus (RV) infection. Since CD103+ DC are essential for specific antiviral responses and their development depends on the growth factor Flt3L, we hypothesized that early-life hyperoxia stimulates Flt3L expression leading to expansion and activation of lung CD103+ DCs and this mediates inflammation. We found that hyperoxia numerically increased and induced proinflammatory transcriptional signatures in neonatal lung CD103+ DCs, as well as CD11bhi DCs. Hyperoxia also increased Flt3L expression. Anti-Flt3L antibody blocked CD103+ DC development in normoxic and hyperoxic conditions, and while it did not affect the baseline number of CD11bhi DCs, it neutralized the effect of hyperoxia on these cells. Anti-Flt3L also inhibited hyperoxia-induced proinflammatory responses to RV. In tracheal aspirates from preterm infants mechanically-ventilated for respiratory distress in the first week of life levels of FLT3L, IL-12p40, IL-12p70 and IFN-γ were higher in infants who went on to develop BPD and FLT3L levels positively correlated with proinflammatory cytokines levels. This work highlights the priming effect of early-life hyperoxia on lung DC development and function and the contribution of Flt3L in driving these effects.
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Affiliation(s)
| | | | | | | | | | - Antonia P. Popova
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, United States
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Saez A, Herrero-Fernandez B, Gomez-Bris R, Sánchez-Martinez H, Gonzalez-Granado JM. Pathophysiology of Inflammatory Bowel Disease: Innate Immune System. Int J Mol Sci 2023; 24:ijms24021526. [PMID: 36675038 PMCID: PMC9863490 DOI: 10.3390/ijms24021526] [Citation(s) in RCA: 213] [Impact Index Per Article: 106.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 12/30/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions.
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Affiliation(s)
- Angela Saez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223 Pozuelo de Alarcón, Spain
| | - Beatriz Herrero-Fernandez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Raquel Gomez-Bris
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Hector Sánchez-Martinez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Jose M. Gonzalez-Granado
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-913908766
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31
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Bosteels C, Van Damme KFA, De Leeuw E, Declercq J, Maes B, Bosteels V, Hoste L, Naesens L, Debeuf N, Deckers J, Cole B, Pardons M, Weiskopf D, Sette A, Weygaerde YV, Malfait T, Vandecasteele SJ, Demedts IK, Slabbynck H, Allard S, Depuydt P, Van Braeckel E, De Clercq J, Martens L, Dupont S, Seurinck R, Vandamme N, Haerynck F, Roychowdhury DF, Vandekerckhove L, Guilliams M, Tavernier SJ, Lambrecht BN. Loss of GM-CSF-dependent instruction of alveolar macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment. Cell Rep Med 2022; 3:100833. [PMID: 36459994 PMCID: PMC9663750 DOI: 10.1016/j.xcrm.2022.100833] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/12/2022] [Accepted: 11/08/2022] [Indexed: 11/17/2022]
Abstract
GM-CSF promotes myelopoiesis and inflammation, and GM-CSF blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar GM-CSF is, however, required for monocytes to differentiate into alveolar macrophages (AMs) that control alveolar homeostasis. By mapping cross-species AM development to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of pro-inflammatory macrophages. In a multi-center, open-label RCT in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides a rationale for further testing of inhaled GM-CSF as a non-invasive treatment to improve alveolar gas exchange and simultaneously boost antiviral immunity in COVID-19. This study is registered at ClinicalTrials.gov (NCT04326920) and EudraCT (2020-001254-22).
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Affiliation(s)
- Cedric Bosteels
- Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
| | - Karel F A Van Damme
- Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
| | - Elisabeth De Leeuw
- Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
| | - Jozefien Declercq
- Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
| | - Bastiaan Maes
- Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
| | - Victor Bosteels
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium; Laboratory of ER Stress and Inflammation, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium
| | - Levi Hoste
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Primary Immunodeficiency Research Lab, Faculty of Medicine and Health Sciences, Ghent University, Ghent 9000, Belgium
| | - Leslie Naesens
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Primary Immunodeficiency Research Lab, Faculty of Medicine and Health Sciences, Ghent University, Ghent 9000, Belgium
| | - Nincy Debeuf
- Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
| | - Julie Deckers
- Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
| | - Basiel Cole
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium
| | - Marion Pardons
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium
| | - Daniela Weiskopf
- Center for Autoimmunity and Inflammation and Center for Infectious Diseases and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Alessandro Sette
- Center for Autoimmunity and Inflammation and Center for Infectious Diseases and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA
| | | | - Thomas Malfait
- Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
| | | | - Ingel K Demedts
- Department of Pulmonary Medicine, AZ Delta General Hospital, 8800 Roeselare, Belgium
| | - Hans Slabbynck
- Department of Pulmonary Medicine, ZNA General Hospital, 2000 Antwerp, Belgium
| | - Sabine Allard
- Department of Internal Medicine, Universitair Ziekenhuis Brussel, 1000 Brussels, Belgium
| | - Pieter Depuydt
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Intensive Care Unit, Ghent University Hospital, 9000 Ghent, Belgium
| | - Eva Van Braeckel
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
| | - Jozefien De Clercq
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Infectious Diseases, Ghent University Hospital, 9000 Ghent, Belgium
| | - Liesbet Martens
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, 9000 Ghent, Belgium
| | - Sam Dupont
- Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
| | - Ruth Seurinck
- Data Mining and Modeling for Biomedicine, VIB-UGent Center for Inflammation Research, 9000 Ghent, Belgium; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, 9000 Ghent, Belgium
| | - Niels Vandamme
- Data Mining and Modeling for Biomedicine, VIB-UGent Center for Inflammation Research, 9000 Ghent, Belgium; VIB Single Cell Core, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium
| | - Filomeen Haerynck
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Primary Immunodeficiency Research Lab, Faculty of Medicine and Health Sciences, Ghent University, Ghent 9000, Belgium
| | | | - Linos Vandekerckhove
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Infectious Diseases, Ghent University Hospital, 9000 Ghent, Belgium
| | - Martin Guilliams
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, 9000 Ghent, Belgium
| | - Simon J Tavernier
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Primary Immunodeficiency Research Lab, Faculty of Medicine and Health Sciences, Ghent University, Ghent 9000, Belgium; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, 9000 Ghent, Belgium; Laboratory of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, 9000 Ghent, Belgium
| | - Bart N Lambrecht
- Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
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Fu C, Ma T, Zhou L, Mi QS, Jiang A. Dendritic Cell-Based Vaccines Against Cancer: Challenges, Advances and Future Opportunities. Immunol Invest 2022; 51:2133-2158. [PMID: 35946383 DOI: 10.1080/08820139.2022.2109486] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
As the most potent professional antigen presenting cells, dendritic cells (DCs) have the ability to activate both naive CD4 and CD8 T cells. Recognized for their exceptional ability to cross-present exogenous antigens to prime naive antigen-specific CD8 T cells, DCs play a critical role in generating CD8 T cell immunity, as well as mediating CD8 T cell tolerance to tumor antigens. Despite the ability to potentiate host CD8 T cell-mediated anti-tumor immunity, current DC-based cancer vaccines have not yet achieved the promised success clinically with the exception of FDA-approved Provenge. Interestingly, recent studies have shown that type 1 conventional DCs (cDC1s) play a critical role in cross-priming tumor-specific CD8 T cells and determining the anti-tumor efficacy of cancer immunotherapies including immune checkpoint blockade (ICB). Together with promising clinical results in neoantigen-based cancer vaccines, there is a great need for DC-based vaccines to be further developed and refined either as monotherapies or in combination with other immunotherapies. In this review, we will present a brief review of DC development and function, discuss recent progress, and provide a perspective on future directions to realize the promising potential of DC-based cancer vaccines.
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Affiliation(s)
- Chunmei Fu
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, Michigan, USA
| | - Tianle Ma
- Department of Computer Science and Engineering, School of Engineering and Computer Science, Oakland University, Rochester, Michigan, USA
| | - Li Zhou
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, Michigan, USA
| | - Qing-Sheng Mi
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, Michigan, USA
| | - Aimin Jiang
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, Michigan, USA
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Papadas A, Deb G, Cicala A, Officer A, Hope C, Pagenkopf A, Flietner E, Morrow ZT, Emmerich P, Wiesner J, Arauz G, Bansal V, Esbona K, Capitini CM, Matkowskyj KA, Deming DA, Politi K, Abrams SI, Harismendy O, Asimakopoulos F. Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment. Cell Rep 2022; 40:111201. [PMID: 35977482 PMCID: PMC9402878 DOI: 10.1016/j.celrep.2022.111201] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 06/10/2022] [Accepted: 07/20/2022] [Indexed: 11/24/2022] Open
Abstract
Stimulatory type 1 conventional dendritic cells (cDC1s) engage in productive interactions with CD8+ effectors along tumor-stroma boundaries. The paradoxical accumulation of “poised” cDC1s within stromal sheets is unlikely to simply reflect passive exclusion from tumor cores. Drawing parallels with embryonic morphogenesis, we hypothesized that invasive margin stromal remodeling generates developmentally conserved cell fate cues that regulate cDC1 behavior. We find that, in human T cell-inflamed tumors, CD8+ T cells penetrate tumor nests, whereas cDC1s are confined within adjacent stroma that recurrently displays site-specific proteolysis of the matrix proteoglycan versican (VCAN), an essential organ-sculpting modification in development. VCAN is necessary, and its proteolytic fragment (matrikine) versikine is sufficient for cDC1 accumulation. Versikine does not influence tumor-seeding pre-DC differentiation; rather, it orchestrates a distinctive cDC1 activation program conferring exquisite sensitivity to DNA sensing, supported by atypical innate lymphoid cells. Thus, peritumoral stroma mimicking embryonic provisional matrix remodeling regulates cDC1 abundance and activity to elicit T cell-inflamed tumor microenvironments. T cell-inflamed tumor microenvironments are a prerequisite for immunotherapy efficacy; however, why some tumors are inflamed and others not remains poorly understood. Papadas et al. link stromal reaction dynamics with T cell-induced inflammation. Peritumoral stroma emulating embryonic provisional matrix remodeling regulates cDC1-NK-CD8+ crosstalk to promote T cell repriming and penetration into tumor nests.
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Affiliation(s)
- Athanasios Papadas
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA; Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Gauri Deb
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Alexander Cicala
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Adam Officer
- Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA; Division of Biomedical Informatics, Department of Medicine, University of California, San Diego (UCSD), Moores Cancer Center, La Jolla, CA, USA; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Chelsea Hope
- Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA; Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Adam Pagenkopf
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Evan Flietner
- Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA; Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Zachary T Morrow
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Philip Emmerich
- Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Joshua Wiesner
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Garrett Arauz
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Varun Bansal
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Karla Esbona
- UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Christian M Capitini
- UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA; Division of Hematology and Oncology, Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, USA
| | - Kristina A Matkowskyj
- UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Dustin A Deming
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA
| | - Katerina Politi
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA; Department of Medicine, Yale School of Medicine, New Haven, CT, USA; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Scott I Abrams
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Olivier Harismendy
- Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA; Division of Biomedical Informatics, Department of Medicine, University of California, San Diego (UCSD), Moores Cancer Center, La Jolla, CA, USA
| | - Fotis Asimakopoulos
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA.
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Di Carlo S, Häcker G, Gentle IE. GM‐CSF suppresses antioxidant signaling and drives IL‐1β secretion through NRF2 downregulation. EMBO Rep 2022; 23:e54226. [PMID: 35695080 PMCID: PMC9346485 DOI: 10.15252/embr.202154226] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 05/11/2022] [Accepted: 05/24/2022] [Indexed: 11/09/2022] Open
Abstract
GM‐CSF is a potent inflammatory cytokine regulating myeloid cell differentiation, hematopoiesis, and various other functions. It is functionally associated with a number of inflammatory pathologies including rheumatoid arthritis and inflammatory bowel disease. GM‐CSF has been found to promote NLRP3‐dependent IL‐1β secretion, which may have a significant role in driving inflammatory pathologies. However, the molecular mechanisms remain unknown. Here, we show that GM‐CSF induces IL‐1β secretion through a ROS‐dependent pathway. TNF is required for reactive oxygen species (ROS) generation that strikingly does not promote NLRP3 activation, but instead drives ubiquitylation of IL‐1β, promoting its cleavage through basal NRLP3 activity. GM‐CSF regulates this pathway through suppression of antioxidant responses via preventing upregulation of NRF2. Thus, the pro‐inflammatory effect of GM‐CSF on IL‐1β is through suppression of antioxidant responses, which leads to ubiquitylation of IL‐1β and enhanced processing. This study highlights the role of metabolic regulation of inflammatory signaling and reveals a novel mechanism for GM‐CSF to promote inflammation.
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Affiliation(s)
- Sara Di Carlo
- Institute of Medical Microbiology and Hygiene Faculty of Medicine Medical Center – University of Freiburg Freiburg Germany
| | - Georg Häcker
- Institute of Medical Microbiology and Hygiene Faculty of Medicine Medical Center – University of Freiburg Freiburg Germany
- BIOSS Centre for Biological Signalling Studies University of Freiburg Freiburg Germany
| | - Ian E Gentle
- Institute of Medical Microbiology and Hygiene Faculty of Medicine Medical Center – University of Freiburg Freiburg Germany
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Kamio N, Yokota A, Tokuda Y, Ogasawara C, Nakano M, Nagao M, Tashiro K, Maekawa T, Onai N, Hirai H. A Novel CD135+ Subset of Mouse Monocytes with a Distinct Differentiation Pathway and Antigen-Presenting Properties. THE JOURNAL OF IMMUNOLOGY 2022; 209:498-509. [DOI: 10.4049/jimmunol.2100024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 05/24/2022] [Indexed: 01/04/2023]
Abstract
Abstract
The mononuclear phagocyte system (MPS), composed of monocytes/macrophages and dendritic cells (DCs), plays a critical role at the interface of the innate and adaptive immune systems. However, the simplicity of MPS has been challenged recently by discoveries of novel cellular components. In the current study, we identified the CD135+ subset of monocytes as a novel class of APCs in mice. CD135+ monocytes were readily found in the bone marrow, spleen, and peripheral blood at steady state, and they expressed markers specific to DCs, including MHC class II and CD209a, along with markers for monocytes/macrophages. In addition, this subset phagocytosed bacteria and activated naive T lymphocytes, fulfilling the criteria for APCs. CD135+ monocytes were derived directly from macrophage DC progenitors, not from common monocyte progenitors or other monocytes, suggesting that these are distinct from conventional monocytes. These findings facilitate our understanding of the MPS network that regulates immune responses for host defense.
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Affiliation(s)
- Naoka Kamio
- *Department of Clinical Laboratory Medicine, Kyoto University Hospital, Kyoto, Japan
- †Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
- ‡Laboratory of Stem Cell Regulation, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Asumi Yokota
- ‡Laboratory of Stem Cell Regulation, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
- §Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH
| | - Yuichi Tokuda
- ¶Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Chie Ogasawara
- ‖Department of Immunology, Kanazawa Medical University, Japan; and
| | - Masakazu Nakano
- ¶Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Miki Nagao
- *Department of Clinical Laboratory Medicine, Kyoto University Hospital, Kyoto, Japan
| | - Kei Tashiro
- ¶Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Taira Maekawa
- †Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
- #Kyoto Prefectural Institute of Public Health and Environment, Kyoto, Japan
| | - Nobuyuki Onai
- ‖Department of Immunology, Kanazawa Medical University, Japan; and
| | - Hideyo Hirai
- *Department of Clinical Laboratory Medicine, Kyoto University Hospital, Kyoto, Japan
- †Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
- ‡Laboratory of Stem Cell Regulation, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
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36
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Piper C, Hainstock E, Yin-Yuan C, Chen Y, Khatun A, Kasmani MY, Evans J, Miller JA, Gorski J, Cui W, Drobyski WR. Single-cell immune profiling reveals a developmentally distinct CD4+ GM-CSF+ T-cell lineage that induces GI tract GVHD. Blood Adv 2022; 6:2791-2804. [PMID: 35015822 PMCID: PMC9092418 DOI: 10.1182/bloodadvances.2021006084] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/29/2021] [Indexed: 11/20/2022] Open
Abstract
Gastrointestinal (GI) tract involvement is a major determinant for subsequent morbidity and mortality arising during graft-versus-host disease (GVHD). CD4+ T cells that produce granulocyte-macrophage colony stimulating factor (GM-CSF) have emerged as central mediators of inflammation in this tissue site as GM-CSF serves as a critical cytokine link between the adaptive and innate arms of the immune system. However, cellular heterogeneity within the CD4+ GM-CSF+ T-cell population due to the concurrent production of other inflammatory cytokines has raised questions as to whether these cells have a common ontology or if a unique CD4+ GM-CSF+ subset exists that differs from other defined T helper subtypes. Using single-cell RNA sequencing analysis (scRNAseq), we identified two CD4+ GM-CSF+ T-cell populations that arose during GVHD and were distinguishable according to the presence or absence of interferon-γ (IFN-γ) coexpression. CD4+ GM-CSF+ IFN-γ- T cells, which emerged preferentially in the colon, had a distinct transcriptional profile, used unique gene regulatory networks, and possessed a nonoverlapping T-cell receptor repertoire compared with CD4+ GM-CSF+ IFN-γ+ T cells as well as all other transcriptionally defined CD4+ T-cell populations in the colon. Functionally, this CD4+ GM-CSF+ T-cell population contributed to pathologic damage in the GI tract that was critically dependent on signaling through the interleukin-17 (IL-7) receptor but was independent of type 1 interferon signaling. Thus, these studies help to unravel heterogeneity within CD4+ GM-CSF+ T cells that arise during GVHD and define a developmentally distinct colitogenic T helper subtype GM-CSF+ subset that mediates immunopathology.
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Affiliation(s)
- Clint Piper
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Emma Hainstock
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Cheng Yin-Yuan
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Yao Chen
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti, Milwaukee, WI; and
| | - Achia Khatun
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti, Milwaukee, WI; and
| | - Moujtaba Y. Kasmani
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti, Milwaukee, WI; and
| | | | | | - Jack Gorski
- Blood Research Institute, Versiti, Milwaukee, WI; and
| | - Weiguo Cui
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti, Milwaukee, WI; and
| | - William R. Drobyski
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
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37
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Mettelman RC, Allen EK, Thomas PG. Mucosal immune responses to infection and vaccination in the respiratory tract. Immunity 2022; 55:749-780. [PMID: 35545027 PMCID: PMC9087965 DOI: 10.1016/j.immuni.2022.04.013] [Citation(s) in RCA: 123] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/12/2022] [Accepted: 04/15/2022] [Indexed: 01/25/2023]
Abstract
The lungs are constantly exposed to inhaled debris, allergens, pollutants, commensal or pathogenic microorganisms, and respiratory viruses. As a result, innate and adaptive immune responses in the respiratory tract are tightly regulated and are in continual flux between states of enhanced pathogen clearance, immune-modulation, and tissue repair. New single-cell-sequencing techniques are expanding our knowledge of airway cellular complexity and the nuanced connections between structural and immune cell compartments. Understanding these varied interactions is critical in treatment of human pulmonary disease and infections and in next-generation vaccine design. Here, we review the innate and adaptive immune responses in the lung and airways following infection and vaccination, with particular focus on influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing SARS-CoV-2 pandemic has put pulmonary research firmly into the global spotlight, challenging previously held notions of respiratory immunity and helping identify new populations at high risk for respiratory distress.
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Affiliation(s)
- Robert C Mettelman
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - E Kaitlynn Allen
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Paul G Thomas
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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38
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Ryu SH, Shin HS, Eum HH, Park JS, Choi W, Na HY, In H, Kim TG, Park S, Hwang S, Sohn M, Kim ED, Seo KY, Lee HO, Lee MG, Chu MK, Park CG. Granulocyte Macrophage-Colony Stimulating Factor Produces a Splenic Subset of Monocyte-Derived Dendritic Cells That Efficiently Polarize T Helper Type 2 Cells in Response to Blood-Borne Antigen. Front Immunol 2022; 12:767037. [PMID: 35069539 PMCID: PMC8778578 DOI: 10.3389/fimmu.2021.767037] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/06/2021] [Indexed: 12/24/2022] Open
Abstract
Dendritic cells (DCs) are key antigen-presenting cells that prime naive T cells and initiate adaptive immunity. Although the genetic deficiency and transgenic overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) signaling were reported to influence the homeostasis of DCs, the in vivo development of DC subsets following injection of GM-CSF has not been analyzed in detail. Among the treatment of mice with different hematopoietic cytokines, only GM-CSF generates a distinct subset of XCR1-33D1- DCs which make up the majority of DCs in the spleen after three daily injections. These GM-CSF-induced DCs (GMiDCs) are distinguished from classical DCs (cDCs) in the spleen by their expression of CD115 and CD301b and by their superior ability to present blood-borne antigen and thus to stimulate CD4+ T cells. Unlike cDCs in the spleen, GMiDCs are exceptionally effective to polarize and expand T helper type 2 (Th2) cells and able to induce allergic sensitization in response to blood-borne antigen. Single-cell RNA sequencing analysis and adoptive cell transfer assay reveal the sequential differentiation of classical monocytes into pre-GMiDCs and GMiDCs. Interestingly, mixed bone marrow chimeric mice of Csf2rb+/+ and Csf2rb-/- demonstrate that the generation of GMiDCs necessitates the cis expression of GM-CSF receptor. Besides the spleen, GMiDCs are generated in the CCR7-independent resident DCs of the LNs and in some peripheral tissues with GM-CSF treatment. Also, small but significant numbers of GMiDCs are generated in the spleen and other tissues during chronic allergic inflammation. Collectively, our present study identifies a splenic subset of CD115hiCD301b+ GMiDCs that possess a strong capacity to promote Th2 polarization and allergic sensitization against blood-borne antigen.
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Affiliation(s)
- Seul Hye Ryu
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.,Immune and Vascular Cell Network Research Center, National Creative Initiatives, Department of Life Sciences, Ewha Womans University, Seoul, South Korea
| | - Hyun Soo Shin
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Hyeon Eum
- Department of Biomedicine and Health Sciences, Graduate School, The Catholic University of Korea, Seoul, South Korea.,Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ji Soo Park
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Wanho Choi
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Young Na
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.,Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyunju In
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Tae-Gyun Kim
- Department of Dermatology, Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Sejung Park
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Soomin Hwang
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Moah Sohn
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun-Do Kim
- Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Kyoung Yul Seo
- Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Hae-Ock Lee
- Department of Biomedicine and Health Sciences, Graduate School, The Catholic University of Korea, Seoul, South Korea.,Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Min-Geol Lee
- Department of Dermatology, Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Min Kyung Chu
- Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Chae Gyu Park
- Laboratory of Immunology, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.,Therapeutic Antibody Research Center, Genuv Inc., Seoul, South Korea.,Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
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Li D, Li J, Liu H, Zhai L, Hu W, Xia N, Tang T, Jiao J, Lv B, Nie S, Hu D, Liao Y, Yang X, Shi G, Cheng X. Pathogenic Tconvs promote inflammatory macrophage polarization through GM‐CSF and exacerbate abdominal aortic aneurysm formation. FASEB J 2022; 36:e22172. [PMID: 35133017 PMCID: PMC9303938 DOI: 10.1096/fj.202101576r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/30/2021] [Accepted: 01/10/2022] [Indexed: 01/05/2023]
Abstract
Abdominal aortic aneurysms (AAAs) elicit massive inflammatory leukocyte recruitment to the aorta. CD4+ T cells, which include regulatory T cells (Tregs) and conventional T cells (Tconvs), are involved in the progression of AAA. Tregs have been reported to limit AAA formation. However, the function and phenotype of the Tconvs found in AAAs remain poorly understood. We characterized aortic Tconvs by bulk RNA sequencing and discovered that Tconvs in aortic aneurysm highly expressed Cxcr6 and Csf2. Herein, we determined that the CXCR6/CXCL16 signaling axis controlled the recruitment of Tconvs to aortic aneurysms. Deficiency of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), encoded by Csf2, markedly inhibited AAA formation and led to a decrease of inflammatory monocytes, due to a reduction of CCL2 expression. Conversely, the exogenous administration of GM‐CSF exacerbated inflammatory monocyte infiltration by upregulating CCL2 expression, resulting in worsened AAA formation. Mechanistically, GM‐CSF upregulated the expression of interferon regulatory factor 5 to promote M1‐like macrophage differentiation in aortic aneurysms. Importantly, we also demonstrated that the GM‐CSF produced by Tconvs enhanced the polarization of M1‐like macrophages and exacerbated AAA formation. Our findings revealed that GM‐CSF, which was predominantly derived from Tconvs in aortic aneurysms, played a pathogenic role in the progression of AAAs and may represent a potential target for AAA treatment.
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Affiliation(s)
- Dan Li
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Jingyong Li
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Henan Liu
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Luna Zhai
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Wangling Hu
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Ni Xia
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Tingting Tang
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Jiao Jiao
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Bingjie Lv
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Shaofang Nie
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Desheng Hu
- Department of Integrated Traditional Chinese and Western Medicine Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Institute of Hematology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Yuhua Liao
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Xiangping Yang
- School of Basic Medicine Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Guo‐Ping Shi
- Department of Medicine Brigham and Women’s Hospital and Harvard Medical School Boston Massachusetts USA
| | - Xiang Cheng
- Department of Cardiology Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
- Key Laboratory for Biological Targeted Therapy of Education Ministry and Hubei Province Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
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40
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Spiteri AG, Wishart CL, Pamphlett R, Locatelli G, King NJC. Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function. Acta Neuropathol 2022; 143:179-224. [PMID: 34853891 PMCID: PMC8742818 DOI: 10.1007/s00401-021-02384-2] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 02/08/2023]
Abstract
In neurological diseases, the actions of microglia, the resident myeloid cells of the CNS parenchyma, may diverge from, or intersect with, those of recruited monocytes to drive immune-mediated pathology. However, defining the precise roles of each cell type has historically been impeded by the lack of discriminating markers and experimental systems capable of accurately identifying them. Our ability to distinguish microglia from monocytes in neuroinflammation has advanced with single-cell technologies, new markers and drugs that identify and deplete them, respectively. Nevertheless, the focus of individual studies on particular cell types, diseases or experimental approaches has limited our ability to connect phenotype and function more widely and across diverse CNS pathologies. Here, we critically review, tabulate and integrate the disease-specific functions and immune profiles of microglia and monocytes to provide a comprehensive atlas of myeloid responses in viral encephalitis, demyelination, neurodegeneration and ischemic injury. In emphasizing the differential roles of microglia and monocytes in the severe neuroinflammatory disease of viral encephalitis, we connect inflammatory pathways common to equally incapacitating diseases with less severe inflammation. We examine these findings in the context of human studies and highlight the benefits and inherent limitations of animal models that may impede or facilitate clinical translation. This enables us to highlight common and contrasting, non-redundant and often opposing roles of microglia and monocytes in disease that could be targeted therapeutically.
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41
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Viswanath DI, Liu HC, Capuani S, Vander Pol RS, Saunders SZ, Chua CYX, Grattoni A. Engineered implantable vaccine platform for continuous antigen-specific immunomodulation. Biomaterials 2022; 281:121374. [PMID: 35066287 PMCID: PMC8865051 DOI: 10.1016/j.biomaterials.2022.121374] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/03/2022] [Accepted: 01/12/2022] [Indexed: 02/03/2023]
Abstract
Cancer vaccines harness the host immune system to generate antigen-specific antitumor immunity for long-term tumor elimination with durable immunomodulation. Commonly investigated strategies reintroduce ex vivo autologous dendritic cells (DCs) but have limited clinical adoption due to difficulty in manufacturing, delivery and low clinical efficacy. To combat this, we designed the "NanoLymph", an implantable subcutaneous device for antigen-specific antitumor immunomodulation. The NanoLymph consists of a dual-reservoir platform for sustained release of immune stimulants via a nanoporous membrane and hydrogel-encapsulated antigens for local immune cell recruitment and activation, respectively. Here, we present the development and characterization of the NanoLymph as well as efficacy validation for immunomodulation in an immunocompetent murine model. Specifically, we established the NanoLymph biocompatibility and mechanical stability. Further, we demonstrated minimally invasive transcutaneous refilling of the drug reservoir in vivo for prolonging drug release duration. Importantly, our study demonstrated that local elution of two drugs (GMCSF and Resiquimod) generates an immune stimulatory microenvironment capable of local DC recruitment and activation and generation of antigen-specific T lymphocytes within 14 days. In summary, the NanoLymph approach can achieve in situ immunomodulation, presenting a viable strategy for therapeutic cancer vaccines.
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Affiliation(s)
- Dixita Ishani Viswanath
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA; Texas A&M University College of Medicine, Bryan & Houston, TX, USA
| | - Hsuan-Chen Liu
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Simone Capuani
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA; University of Chinese Academy of Science (UCAS), Shijingshan, 19 Yuquan Road, Beijing, 100049, China
| | | | | | | | - Alessandro Grattoni
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA; Department of Surgery, Houston Methodist Hospital, Houston, TX, USA; Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX, USA.
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42
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IFNγ and GM-CSF control complementary differentiation programs in the monocyte-to-phagocyte transition during neuroinflammation. Nat Immunol 2022; 23:217-228. [DOI: 10.1038/s41590-021-01117-7] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 12/10/2021] [Indexed: 02/06/2023]
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43
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Ju YJ, Lee KM, Kim G, Kye YC, Kim HW, Chu H, Park BC, Cho JH, Chang PS, Han SH, Yun CH. Change of Dendritic Cell Subsets Involved in Protection Against Listeria monocytogenes Infection in Short-Term-Fasted Mice. Immune Netw 2022; 22:e16. [PMID: 35573152 PMCID: PMC9066004 DOI: 10.4110/in.2022.22.e16] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 02/24/2022] [Accepted: 03/13/2022] [Indexed: 12/01/2022] Open
Abstract
The gastrointestinal tract is the first organ directly affected by fasting. However, little is known about how fasting influences the intestinal immune system. Intestinal dendritic cells (DCs) capture antigens, migrate to secondary lymphoid organs, and provoke adaptive immune responses. We evaluated the changes of intestinal DCs in mice with short-term fasting and their effects on protective immunity against Listeria monocytogenes (LM). Fasting induced an increased number of CD103+CD11b− DCs in both small intestinal lamina propria (SILP) and mesenteric lymph nodes (mLN). The SILP CD103+CD11b− DCs showed proliferation and migration, coincident with increased levels of GM-CSF and C-C chemokine receptor type 7, respectively. At 24 h post-infection with LM, there was a significant reduction in the bacterial burden in the spleen, liver, and mLN of the short-term-fasted mice compared to those fed ad libitum. Also, short-term-fasted mice showed increased survival after LM infection compared with ad libitum-fed mice. It could be that significantly high TGF-β2 and Aldh1a2 expression in CD103+CD11b− DCs in mice infected with LM might affect to increase of Foxp3+ regulatory T cells. Changes of major subset of DCs from CD103+ to CD103− may induce the increase of IFN-γ–producing cells with forming Th1-biased environment. Therefore, the short-term fasting affects protection against LM infection by changing major subset of intestinal DCs from tolerogenic to Th1 immunogenic.
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Affiliation(s)
- Young-Jun Ju
- Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
| | - Kyung-Min Lee
- Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
| | - Girak Kim
- Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
| | - Yoon-Chul Kye
- Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
| | - Han Wool Kim
- Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
| | - Hyuk Chu
- Division of Zoonotic and Vector Borne Disease Research, Center for Infectious Disease Research, National Institute of Health, Cheongju 28159, Korea
| | - Byung-Chul Park
- Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang 25354, Korea
| | - Jae-Ho Cho
- Department of Microbiology and Immunology, Chonnam National University Medical School, Hwasun Hospital, Hwasun 58128, Korea
| | - Pahn-Shick Chang
- Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
- Center for Agricultural Microorganism and Enzyme, Seoul National University, Seoul 08826, Korea
- Center for Food and Biocenvergence, Seoul National University, Seoul 08826, Korea
| | - Seung Hyun Han
- Department of Oral Microbiology and Immunology, and Dental Research Institute, School of Dentistry, Seoul National University, Seoul 08826, Korea
| | - Cheol-Heui Yun
- Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
- Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang 25354, Korea
- Center for Food and Biocenvergence, Seoul National University, Seoul 08826, Korea
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44
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Luciani C, Hager FT, Cerovic V, Lelouard H. Dendritic cell functions in the inductive and effector sites of intestinal immunity. Mucosal Immunol 2022; 15:40-50. [PMID: 34465895 DOI: 10.1038/s41385-021-00448-w] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/09/2021] [Accepted: 08/15/2021] [Indexed: 02/04/2023]
Abstract
The intestine is constantly exposed to foreign antigens, which are mostly innocuous but can sometimes be harmful. Therefore, the intestinal immune system has the delicate task of maintaining immune tolerance to harmless food antigens while inducing tailored immune responses to pathogens and regulating but tolerating the microbiota. Intestinal dendritic cells (DCs) play a central role in these functions as sentinel cells able to prime and polarize the T cell responses. DCs are deployed throughout the intestinal mucosa but with local specializations along the gut length and between the diffuse effector sites of the gut lamina propria (LP) and the well-organized immune inductive sites comprising isolated lymphoid follicles (ILFs), Peyer's patches (PPs), and other species-specific gut-associated lymphoid tissues (GALTs). Understanding the specificities of each intestinal DC subset, how environmental factors influence DC functions, and how these can be modulated is key to harnessing the therapeutic potential of mucosal adaptive immune responses, whether by enhancing the efficacy of mucosal vaccines or by increasing tolerogenic responses in inflammatory disorders. In this review, we summarize recent findings related to intestinal DCs in steady state and upon inflammation, with a special focus on their functional specializations, highly dependent on their microenvironment.
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Affiliation(s)
| | | | - Vuk Cerovic
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany.
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45
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Das A, Chauhan KS, Kumar H, Tailor P. Mutation in Irf8 Gene ( Irf8R294C ) Impairs Type I IFN-Mediated Antiviral Immune Response by Murine pDCs. Front Immunol 2021; 12:758190. [PMID: 34867997 PMCID: PMC8635750 DOI: 10.3389/fimmu.2021.758190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/25/2021] [Indexed: 12/01/2022] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are the key producers of type I interferons (IFNs), thus playing a central role in initiating antiviral immune response. Besides robust type I IFN production, pDCs also act as antigen presenting cells post immunogenic stimulation. Transcription factor Irf8 is indispensable for the development of both pDC and cDC1 subset. However, the mechanism underlying the differential regulation by IRF8 in cDC1- and pDC-specific genomic architecture of developmental pathways still remains to be fully elucidated. Previous studies indicated that the Irf8R294C mutation specifically abrogates development of cDC1 without affecting that of pDC. In the present study using RNA-seq based approach, we have found that though the point mutation Irf8R294C did not affect pDC development, it led to defective type I IFN production, thus resulting in inefficient antiviral response. This observation unraveled the distinctive roles of IRF8 in these two subpopulations—regulating the development of cDC1 whereas modulating the functionality of pDCs without affecting development. We have reported here that Irf8R294C mutation also caused defect in production of ISGs as well as defective upregulation of costimulatory molecules in pDCs in response to NDV infection (or CpG stimulation). Through in vivo studies, we demonstrated that abrogation of type I IFN production was concomitant with reduced upregulation of costimulatory molecules in pDCs and increased NDV burden in IRF8R294C mice in comparison with wild type, indicating inefficient viral clearance. Further, we have also shown that Irf8R294C mutation abolished the activation of type I IFN promoter by IRF8, justifying the low level of type I IFN production. Taken together, our study signifies that the single point mutation in Irf8, Irf8R294C severely compromised type I IFN-mediated immune response by murine pDCs, thereby causing impairment in antiviral immunity.
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Affiliation(s)
- Annesa Das
- Laboratory of Innate Immunity, National Institute of Immunology, New Delhi, India
| | | | - Himanshu Kumar
- Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, India
| | - Prafullakumar Tailor
- Laboratory of Innate Immunity, National Institute of Immunology, New Delhi, India.,Special Centre for Systems Medicine (SCSM), Jawaharlal Nehru University, New Delhi, India
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46
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Wu Z, Hu T, Chintoan-Uta C, Macdonald J, Stevens MP, Sang H, Hume DA, Kaiser P, Balic A. Development of novel reagents to chicken FLT3, XCR1 and CSF2R for the identification and characterization of avian conventional dendritic cells. Immunology 2021; 165:171-194. [PMID: 34767637 DOI: 10.1111/imm.13426] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/30/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Conventional dendritic cells (cDC) are bone marrow-derived immune cells that play a central role in linking innate and adaptive immunity. cDCs efficiently uptake, process and present antigen to naïve T cells, driving clonal expansion of antigen-specific T-cell responses. In chicken, vital reagents are lacking for the efficient and precise identification of cDCs. In this study, we have developed several novel reagents for the identification and characterization of chicken cDCs. Chicken FLT3 cDNA was cloned and a monoclonal antibody to cell surface FLT3 was generated. This antibody identified a distinct FLT3HI splenic subset which lack expression of signature markers for B cells, T cells or monocyte/macrophages. By combining anti-FLT3 and CSF1R-eGFP transgenic expression, three major populations within the mononuclear phagocyte system were identified in the spleen. The cDC1 subset of mammalian cDCs express the chemokine receptor XCR1. To characterize chicken cDCs, a synthetic chicken chemokine (C motif) ligand (XCL1) peptide conjugated to Alexa Fluor 647 was developed (XCL1AF647 ). Flow cytometry staining of XCL1AF647 on splenocytes showed that all chicken FLT3HI cells exclusively express XCR1, supporting the hypothesis that this population comprises bona fide chicken cDCs. Further analysis revealed that chicken cDCs expressed CSF1R but lacked the expression of CSF2R. Collectively, the cell surface phenotypes of chicken cDCs were partially conserved with mammalian XCR1+ cDC1, with distinct differences in CSF1R and CSF2R expression compared with mammalian orthologues. These original reagents allow the efficient identification of chicken cDCs to investigate their important roles in the chicken immunity and diseases.
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Affiliation(s)
- Zhiguang Wu
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, UK
| | - Tuanjun Hu
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, UK
| | | | - Joni Macdonald
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, UK
| | - Mark P Stevens
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, UK
| | - Helen Sang
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, UK
| | - David A Hume
- Translational Research Institute, Mater Research Institute-University of Queensland, Woolloongabba, Qld, Australia
| | - Pete Kaiser
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, UK
| | - Adam Balic
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, UK
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47
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Abstract
Granulocyte macrophage-colony stimulating factor (GM-CSF) was originally identified as a growth factor for its ability to promote the proliferation and differentiation in vitro of bone marrow progenitor cells into granulocytes and macrophages. Many preclinical studies, using GM-CSF deletion or depletion approaches, have demonstrated that GM-CSF has a wide range of biological functions, including the mediation of inflammation and pain, indicating that it can be a potential target in many inflammatory and autoimmune conditions. This review provides a brief overview of GM-CSF biology and signaling, and summarizes the findings from preclinical models of a range of inflammatory and autoimmune disorders and the latest clinical trials targeting GM-CSF or its receptor in these disorders.
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Affiliation(s)
- Adrian A Achuthan
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050, Australia.
| | - Kevin M C Lee
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050, Australia
| | - John A Hamilton
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050, Australia; Australian Institute for Musculoskeletal Science, St Albans, Victoria 3021, Australia
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48
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Ingelfinger F, De Feo D, Becher B. GM-CSF: Master regulator of the T cell-phagocyte interface during inflammation. Semin Immunol 2021; 54:101518. [PMID: 34763973 DOI: 10.1016/j.smim.2021.101518] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/23/2021] [Indexed: 12/21/2022]
Abstract
The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) was sequentially redefined during the past decades. Originally described as a hematopoietic growth factor for myelopoiesis, GM-CSF was recognized as a central mediator of inflammation bridging the innate and adaptive arms of the immune system. Phagocytes sensing GM-CSF adapt an inflammatory phenotype and facilitate pathogen clearance. However, in the context of chronic tissue inflammation, GM-CSF secreted by tissue-invading lymphocytes has detrimental effects by licensing tissue damage and hyperinflammation. Accordingly, therapeutic intervention at the T cell-phagocyte interface represents an attractive target to ameliorate disease progression and immunopathology. Although GM-CSF is largely dispensable for steady state myelopoiesis, dysregulation, as seen in chronic inflammatory diseases, may however lead to disrupted haematopoiesis and long-term effects on bone marrow output. Here, we will survey the role of GM-CSF during inflammation, discuss the extent to which GM-CSF-secreting T cells, debate their introduction as a separate T cell lineage and explore current and future clinical implications of GM-CSF in human disease settings.
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Affiliation(s)
- Florian Ingelfinger
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland; Department of Neurology, University Hospital Zurich, Zurich, Switzerland
| | - Donatella De Feo
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
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49
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TLR or NOD receptor signaling skews monocyte fate decision via distinct mechanisms driven by mTOR and miR-155. Proc Natl Acad Sci U S A 2021; 118:2109225118. [PMID: 34686603 DOI: 10.1073/pnas.2109225118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2021] [Indexed: 12/20/2022] Open
Abstract
Monocytes are rapidly recruited to inflamed tissues where they differentiate into monocyte-derived macrophages (mo-mac) or dendritic cells (mo-DC). At infection sites, monocytes encounter a broad range of microbial motifs. How pathogen recognition impacts monocyte fate decision is unclear. Here, we show, using an in vitro model allowing the simultaneous differentiation of human mo-mac and mo-DC, that viruses promote mo-mac while Mycobacteria favor mo-DC differentiation. Mechanistically, we found that pathogen sensing through toll-like receptor (TLR) ligands increases mo-mac differentiation via mTORC1. By contrast, nucleotide-binding oligomerization domain (NOD) ligands favor mo-DC through the induction of TNF-α secretion and miR-155 expression. We confirmed these results in vivo, in mouse skin and by analyzing transcriptomic data from human individuals. Overall, our findings allow a better understanding of the molecular control of monocyte differentiation and of monocyte plasticity upon pathogen sensing.
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50
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Su X, Xu Y, Fox GC, Xiang J, Kwakwa KA, Davis JL, Belle JI, Lee WC, Wong WH, Fontana F, Hernandez-Aya LF, Kobayashi T, Tomasson HM, Su J, Bakewell SJ, Stewart SA, Egbulefu C, Karmakar P, Meyer MA, Veis DJ, DeNardo DG, Lanza GM, Achilefu S, Weilbaecher KN. Breast cancer-derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment. J Clin Invest 2021; 131:e145296. [PMID: 34520398 PMCID: PMC8516467 DOI: 10.1172/jci145296] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 08/31/2021] [Indexed: 12/13/2022] Open
Abstract
Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell-produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Wing H. Wong
- Department of Medicine
- Edison Family Center for Genome Sciences and Systems Biology
| | | | | | | | | | | | | | - Sheila A. Stewart
- Department of Medicine
- Department of Cell Biology and Physiology
- Siteman Cancer Center
| | | | | | | | - Deborah J. Veis
- Department of Medicine
- Musculoskeletal Research Center, Histology and Morphometry Core, and
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - David G. DeNardo
- Department of Medicine
- Siteman Cancer Center
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | | | | | - Katherine N. Weilbaecher
- Department of Medicine
- Department of Cell Biology and Physiology
- Siteman Cancer Center
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
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