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Nouari W, Aribi M. Innate lymphoid cells, immune functional dynamics, epithelial parallels, and therapeutic frontiers in infections. Int Rev Immunol 2025:1-28. [PMID: 40242974 DOI: 10.1080/08830185.2025.2490233] [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: 04/03/2024] [Revised: 02/19/2025] [Accepted: 04/02/2025] [Indexed: 04/18/2025]
Abstract
Innate lymphoid cells (ILCs) have emerged as pivotal players in the field of immunology, expanding our understanding of innate immunity beyond conventional paradigms. This comprehensive review delves into the multifaceted world of ILCs, beginning with their serendipitous discovery and traversing their ontogeny and heterogeneity. We explore the distinct subsets of ILCs unraveling their intriguing plasticity, which adds a layer of complexity to their functional repertoire. As we journey through the functional activities of ILCs, we address their role in immune responses against various infections, categorizing their interactions with helminthic parasites, bacterial pathogens, fungal infections, and viral invaders. Notably, this review offers a detailed examination of ILCs in the context of specific infections, such as Mycobacterium tuberculosis, Citrobacter rodentium, Clostridium difficile, Salmonella typhimurium, Helicobacter pylori, Listeria monocytogenes, Staphylococcus aureus, Pseudomonas aeruginosa, Influenza virus, Cytomegalovirus, Herpes simplex virus, and severe acute respiratory syndrome coronavirus 2. This selection aimed for a comprehensive exploration of ILCs in various infectious contexts, opting for microorganisms based on extensive research findings rather than considerations of virulence or emergence. Furthermore, we raise intriguing questions about the potential immune functional resemblances between ILCs and epithelial cells, shedding light on their interconnectedness within the mucosal microenvironment. The review culminates in a critical assessment of the therapeutic prospects of targeting ILCs during infection, emphasizing their promise as novel immunotherapeutic targets. Nevertheless, due to their recent discovery and evolving understanding, effectively manipulating ILCs is challenging. Ensuring specificity and safety while evaluating long-term effects in clinical settings will be crucial.
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Affiliation(s)
- Wafa Nouari
- Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, Tlemcen, Algeria
| | - Mourad Aribi
- Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, Tlemcen, Algeria
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2
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Deshmukh H, Whitsett J, Zacharias W, Way SS, Martinez FD, Mizgerd J, Pryhuber G, Ambalavanan N, Bacharier L, Natarajan A, Tamburro R, Lin S, Randolph A, Nino G, Mejias A, Ramilo O. Impact of Viral Lower Respiratory Tract Infection (LRTI) in Early Childhood (0-2 Years) on Lung Growth and Development and Lifelong Trajectories of Pulmonary Health: A National Institutes of Health (NIH) Workshop Summary. Pediatr Pulmonol 2025; 60:e27357. [PMID: 39565217 PMCID: PMC11740654 DOI: 10.1002/ppul.27357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 10/14/2024] [Accepted: 10/16/2024] [Indexed: 11/21/2024]
Abstract
Viral lower respiratory tract infections (LRTI) are ubiquitous in early life. They are disproportionately severe in infants and toddlers (0-2 years), leading to more than 100,000 hospitalizations in the United States per year. The recent relative resilience to severe Coronavirus disease (COVID-19) observed in young children is surprising. These observations, taken together, underscore current knowledge gaps in the pathogenesis of viral lower respiratory tract diseases in young children and respiratory developmental immunology. Further, early-life respiratory viral infections could have a lasting impact on lung development with potential life-long pulmonary sequelae. Modern molecular methods, including high-resolution spatial and single-cell technologies, in concert with longitudinal observational studies beginning in the prenatal period and continuing into early childhood, promise to elucidate developmental pulmonary and immunophenotypes following early-life viral infections and their impact on trajectories of future respiratory health. In November 2019, under the auspices of a multi-disciplinary Workshop convened by the National Heart Lung Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, experts came together to highlight the challenges of respiratory viral infections, particularly in early childhood, and emphasize the knowledge gaps in immune, virological, developmental, and clinical factors that contribute to disease severity and long-term pulmonary morbidity from viral LRTI in children. We hope that the scientific community will view these challenges in clinical care on pulmonary health trajectories and disease burden not as a window of susceptibility but as a window of opportunity.
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Affiliation(s)
- Hitesh Deshmukh
- Divisions of NeonatologyUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Pulmonary Biology, and Infectious DiseasesUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Medical Scientist Training ProgramUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
| | - Jeffrey Whitsett
- Divisions of NeonatologyUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Pulmonary Biology, and Infectious DiseasesUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
| | - William Zacharias
- Pulmonary Biology, and Infectious DiseasesUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Medical Scientist Training ProgramUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
| | - Sing Sing Way
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Cincinnati Children's Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
| | - Fernando D. Martinez
- Asthma and Airway Disease Research CenterThe University of ArizonaTucsonArizonaUSA
| | - Joseph Mizgerd
- Pulmonary CenterBoston University School of MedicineBostonMassachusettsUSA
| | - Gloria Pryhuber
- Division of Neonatology, Department of Pediatrics, Golisano Children's HospitalUniversity of Rochester Medical CenterRochesterNew YorkUSA
| | - Namasivayam Ambalavanan
- Division of Neonatology, Department of PediatricsUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Leonard Bacharier
- Department of PediatricsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | | | - Robert Tamburro
- Eunice Kennedy Shriver National Institutes of Child Health and Human DevelopmentBethesdaMarylandUSA
| | - Sara Lin
- National Heart, Lung and Blood InstituteBethesdaMarylandUSA
| | - Adrienne Randolph
- Departments of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Departments of Anaesthesia and Harvard Medical SchoolCambridgeMassachusettsUSA
- Pediatrics, Harvard Medical SchoolCambridgeMassachusettsUSA
| | - Gustavo Nino
- Division of Pediatric Pulmonary and Sleep Medicine, Children's National HospitalGeorge Washington UniversityWashingtonD.C.USA
| | - Asuncion Mejias
- Department of Infectious DiseasesSt. Jude Children's Research HospitalMemphisTennesseeUSA
| | - Octavio Ramilo
- Department of Infectious DiseasesSt. Jude Children's Research HospitalMemphisTennesseeUSA
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3
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Araujo LP, Edwards M, Irie K, Huang Y, Kawano Y, Tran A, De Michele S, Bhagat G, Wang HH, Ivanov II. Context-dependent role of group 3 innate lymphoid cells in mucosal protection. Sci Immunol 2024; 9:eade7530. [PMID: 39151019 PMCID: PMC11586228 DOI: 10.1126/sciimmunol.ade7530] [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: 09/11/2022] [Accepted: 07/22/2024] [Indexed: 08/18/2024]
Abstract
How group 3 innate lymphoid cells (ILC3s) regulate mucosal protection in the presence of T cells remains poorly understood. Here, we examined ILC3 function in intestinal immunity using ILC3-deficient mice that maintain endogenous T cells, T helper 17 (TH17) cells, and secondary lymphoid organs. ILC3s were dispensable for generation of TH17 and TH22 cell responses to commensal and pathogenic bacteria, and absence of ILC3s did not affect IL-22 production by CD4 T cells before or during infection. However, despite the presence of IL-22-producing T cells, ILC3s and ILC3-derived IL-22 were required for maintaining homeostatic functions of the intestinal epithelium. T cell-sufficient, ILC3-deficient mice were capable of pathogen clearance and survived infection with a low dose of Citrobacter rodentium. However, ILC3s promoted pathogen tolerance at early time points of infection by activating tissue-protective immune pathways. Consequently, ILC3s were indispensable for survival after high-dose infection. Our results demonstrate a context-dependent role for ILC3s in immune-sufficient animals and provide a blueprint for uncoupling of ILC3 and TH17 cell functions.
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Affiliation(s)
- Leandro P. Araujo
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Madeline Edwards
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Koichiro Irie
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Yiming Huang
- Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY, USA
- Department of Systems Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Yoshinaga Kawano
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Alexander Tran
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Simona De Michele
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Govind Bhagat
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Harris H. Wang
- Department of Systems Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Ivaylo I. Ivanov
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Columbia University Digestive and Liver Diseases Research Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
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4
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Dumitru A, Matei E, Cozaru GC, Chisoi A, Alexandrescu L, Popescu RC, Butcaru MP, Dumitru E, Rugină S, Tocia C. Endotoxin Inflammatory Action on Cells by Dysregulated-Immunological-Barrier-Linked ROS-Apoptosis Mechanisms in Gut-Liver Axis. Int J Mol Sci 2024; 25:2472. [PMID: 38473721 DOI: 10.3390/ijms25052472] [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: 12/27/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
Our study highlighted the immune changes by pro-inflammatory biomarkers in the gut-liver-axis-linked ROS-cell death mechanisms in chronic and acute inflammations when gut cells are exposed to endotoxins in patients with hepatic cirrhosis or steatosis. In duodenal tissue samples, gut immune barrier dysfunction was analyzed by pro-inflammatory biomarker expressions, oxidative stress, and cell death by flow cytometry methods. A significant innate and adaptative immune system reaction was observed as result of persistent endotoxin action in gut cells in chronic inflammation tissue samples recovered from hepatic cirrhosis with the A-B child stage. Instead, in patients with C child stage of HC, the endotoxin tolerance was installed in cells, characterized by T lymphocyte silent activation and increased Th1 cytokines expression. Interesting mechanisms of ROS-cell death were observed in chronic and acute inflammation samples when gut cells were exposed to endotoxins and immune changes in the gut-liver axis. Late apoptosis represents the chronic response to injury induction by the gut immune barrier dysfunction, oxidative stress, and liver-dysregulated barrier. Meanwhile, necrosis represents an acute and severe reply to endotoxin action on gut cells when the immune system reacts to pro-inflammatory Th1 and Th2 cytokines releasing, offering protection against PAMPs/DAMPs by monocytes and T lymphocyte activation. Flow cytometric analysis of pro-inflammatory biomarkers linked to oxidative stress-cell death mechanisms shown in our study recommends laboratory techniques in diagnostic fields.
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Affiliation(s)
- Andrei Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Elena Matei
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Georgeta Camelia Cozaru
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Anca Chisoi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Luana Alexandrescu
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Răzvan Cătălin Popescu
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Mihaela Pundiche Butcaru
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Eugen Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Sorin Rugină
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Cristina Tocia
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
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5
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Ou Q, Power R, Griffin MD. Revisiting regulatory T cells as modulators of innate immune response and inflammatory diseases. Front Immunol 2023; 14:1287465. [PMID: 37928540 PMCID: PMC10623442 DOI: 10.3389/fimmu.2023.1287465] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 10/05/2023] [Indexed: 11/07/2023] Open
Abstract
Regulatory T cells (Treg) are known to be critical for the maintenance of immune homeostasis by suppressing the activation of auto- or allo-reactive effector T cells through a diverse repertoire of molecular mechanisms. Accordingly, therapeutic strategies aimed at enhancing Treg numbers or potency in the setting of autoimmunity and allogeneic transplants have been energetically pursued and are beginning to yield some encouraging outcomes in early phase clinical trials. Less well recognized from a translational perspective, however, has been the mounting body of evidence that Treg directly modulate most aspects of innate immune response under a range of different acute and chronic disease conditions. Recognizing this aspect of Treg immune modulatory function provides a bridge for the application of Treg-based therapies to common medical conditions in which organ and tissue damage is mediated primarily by inflammation involving myeloid cells (mononuclear phagocytes, granulocytes) and innate lymphocytes (NK cells, NKT cells, γδ T cells and ILCs). In this review, we comprehensively summarize pre-clinical and human research that has revealed diverse modulatory effects of Treg and specific Treg subpopulations on the range of innate immune cell types. In each case, we emphasize the key mechanistic insights and the evidence that Treg interactions with innate immune effectors can have significant impacts on disease severity or treatment. Finally, we discuss the opportunities and challenges that exist for the application of Treg-based therapeutic interventions to three globally impactful, inflammatory conditions: type 2 diabetes and its end-organ complications, ischemia reperfusion injury and atherosclerosis.
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Affiliation(s)
- Qifeng Ou
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland
| | - Rachael Power
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland
| | - Matthew D. Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland
- Nephrology Department, Galway University Hospitals, Saolta University Healthcare Group, Galway, Ireland
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6
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Asseri AH, Bakhsh T, Abuzahrah SS, Ali S, Rather IA. The gut dysbiosis-cancer axis: illuminating novel insights and implications for clinical practice. Front Pharmacol 2023; 14:1208044. [PMID: 37361202 PMCID: PMC10288883 DOI: 10.3389/fphar.2023.1208044] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 05/31/2023] [Indexed: 06/28/2023] Open
Abstract
The human intestinal microbiota, also known as the gut microbiota, comprises more than 100 trillion organisms, mainly bacteria. This number exceeds the host body cells by a factor of ten. The gastrointestinal tract, which houses 60%-80% of the host's immune cells, is one of the largest immune organs. It maintains systemic immune homeostasis in the face of constant bacterial challenges. The gut microbiota has evolved with the host, and its symbiotic state with the host's gut epithelium is a testament to this co-evolution. However, certain microbial subpopulations may expand during pathological interventions, disrupting the delicate species-level microbial equilibrium and triggering inflammation and tumorigenesis. This review highlights the impact of gut microbiota dysbiosis on the development and progression of certain types of cancers and discusses the potential for developing new therapeutic strategies against cancer by manipulating the gut microbiota. By interacting with the host microbiota, we may be able to enhance the effectiveness of anticancer therapies and open new avenues for improving patient outcomes.
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Affiliation(s)
- Amer H. Asseri
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Center for Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Tahani Bakhsh
- Department of Biology, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | | | - Sajad Ali
- Department of Biotechnology, Yeungnam University, Gyeongsan, Republic of Korea
| | - Irfan A. Rather
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Centre of Excellence in Bionanoscience Research, King Abdulaziz University, Jeddah, Saudi Arabia
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7
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Verma M, McKay J, Verma D. Role of epigenetics in innate lymphoid cells. Epigenomics 2023; 15:615-618. [PMID: 37435673 DOI: 10.2217/epi-2023-0221] [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] [Indexed: 07/13/2023] Open
Abstract
Epigenetics plays a crucial role in gene regulation and cell function without changing the DNA sequence. The process of differentiation in eukaryotes during cellular morphogenesis is a paradigm of epigenetic change; stem cells develop into pluripotent cell lines in the embryo, eventually becoming terminally developed cells. Recently, epigenetic changes were shown to play an important role in immune cell development, activation and differentiation, which impacts chromatin remodeling, DNA methylation, post-translational histone modifications and small or lncRNA engagement. Innate lymphoid cells (ILCs) are newly identified immune cells that lack antigen receptors. ILCs differentiate from hematopoietic stem cells via multipotent progenitor stages. In this editorial, the authors discuss the epigenetic regulation of ILC differentiation and function.
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Affiliation(s)
- Mukesh Verma
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA
| | - Jerome McKay
- Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Divya Verma
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA
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Singh TP, Kadyan S, Devi H, Park G, Nagpal R. Gut microbiome as a therapeutic target for liver diseases. Life Sci 2023; 322:121685. [PMID: 37044173 DOI: 10.1016/j.lfs.2023.121685] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/27/2023] [Accepted: 04/05/2023] [Indexed: 04/14/2023]
Abstract
The prominent role of gut in regulating the physiology of different organs in a human body is increasingly acknowledged, to which the bidirectional communication between gut and liver is no exception. Liver health is modulated via different key components of gut-liver axis. The gut-derived products mainly generated from dietary components, microbial metabolites, toxins, or other antigens are sensed and transported to the liver through portal vein to which liver responds by secreting bile acids and antibodies. Therefore, maintaining a healthy gut microbiome can promote homeostasis of this gut-liver axis by regulating the intestinal barrier function and reducing the antigenic molecules. Conversely, liver secretions also regulate the gut microbiome composition. Disturbed homeostasis allows luminal antigens to reach liver leading to impaired liver functioning and instigating liver disorders. The perturbations in gut microbiome, permeability, and bile acid pool have been associated with several liver disorders, although precise mechanisms remain largely unresolved. Herein, we discuss functional fingerprints of a healthy gut-liver axis while contemplating mechanistic understanding of pathophysiology of liver diseases and plausible role of gut dysbiosis in different diseased states of liver. Further, novel therapeutic approaches to prevent the severity of liver disorders are discussed in this review.
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Affiliation(s)
- Tejinder Pal Singh
- Department of Dairy Microbiology, College of Dairy Science and Technology, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana 125004, India
| | - Saurabh Kadyan
- Department of Nutrition and Integrative Physiology, College of Health and Human Sciences, Florida State University, Tallahassee, FL 32306, USA
| | - Harisha Devi
- Department of Dairy Microbiology, College of Dairy Science and Technology, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana 125004, India
| | - Gwoncheol Park
- Department of Nutrition and Integrative Physiology, College of Health and Human Sciences, Florida State University, Tallahassee, FL 32306, USA
| | - Ravinder Nagpal
- Department of Nutrition and Integrative Physiology, College of Health and Human Sciences, Florida State University, Tallahassee, FL 32306, USA.
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9
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Ng WL, Ansell SM, Mondello P. Insights into the tumor microenvironment of B cell lymphoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:362. [PMID: 36578079 PMCID: PMC9798587 DOI: 10.1186/s13046-022-02579-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 12/20/2022] [Indexed: 12/30/2022]
Abstract
The standard therapies in lymphoma have predominantly focused on targeting tumor cells with less of a focus on the tumor microenvironment (TME), which plays a critical role in favoring tumor growth and survival. Such an approach may result in increasingly refractory disease with progressively reduced responses to subsequent treatments. To overcome this hurdle, targeting the TME has emerged as a new therapeutic strategy. The TME consists of T and B lymphocytes, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and other components. Understanding the TME can lead to a comprehensive approach to managing lymphoma, resulting in therapeutic strategies that target not only cancer cells, but also the supportive environment and thereby ultimately improve survival of lymphoma patients. Here, we review the normal function of different components of the TME, the impact of their aberrant behavior in B cell lymphoma and the current TME-direct therapeutic avenues.
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Affiliation(s)
- Wern Lynn Ng
- grid.66875.3a0000 0004 0459 167XDivision of Hematology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905 USA
| | - Stephen M. Ansell
- grid.66875.3a0000 0004 0459 167XDivision of Hematology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905 USA
| | - Patrizia Mondello
- grid.66875.3a0000 0004 0459 167XDivision of Hematology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905 USA
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10
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Stanbery AG, Shuchi Smita, Jakob von Moltke, Tait Wojno ED, Ziegler SF. TSLP, IL-33, and IL-25: Not just for allergy and helminth infection. J Allergy Clin Immunol 2022; 150:1302-1313. [PMID: 35863509 PMCID: PMC9742339 DOI: 10.1016/j.jaci.2022.07.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/16/2022] [Accepted: 07/08/2022] [Indexed: 12/14/2022]
Abstract
The release of cytokines from epithelial and stromal cells is critical for the initiation and maintenance of tissue immunity. Three such cytokines, thymic stromal lymphopoietin, IL-33, and IL-25, are important regulators of type 2 immune responses triggered by parasitic worms and allergens. In particular, these cytokines activate group 2 innate lymphoid cells, TH2 cells, and myeloid cells, which drive hallmarks of type 2 immunity. However, emerging data indicate that these tissue-associated cytokines are not only involved in canonical type 2 responses but are also important in the context of viral infections, cancer, and even homeostasis. Here, we provide a brief review of the roles of thymic stromal lymphopoietin, IL-33, and IL-25 in diverse immune contexts, while highlighting their relative contributions in tissue-specific responses. We also emphasize a biologically motivated framework for thinking about the integration of multiple immune signals, including the 3 featured in this review.
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Affiliation(s)
| | - Shuchi Smita
- Department of Immunology, University of Washington, Seattle, Wash
| | - Jakob von Moltke
- Department of Immunology, University of Washington, Seattle, Wash
| | | | - Steven F Ziegler
- Department of Immunology, University of Washington, Seattle, Wash; Benaroya Research Institute, Seattle, Wash.
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11
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Kawano Y, Edwards M, Huang Y, Bilate AM, Araujo LP, Tanoue T, Atarashi K, Ladinsky MS, Reiner SL, Wang HH, Mucida D, Honda K, Ivanov II. Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome. Cell 2022; 185:3501-3519.e20. [PMID: 36041436 PMCID: PMC9556172 DOI: 10.1016/j.cell.2022.08.005] [Citation(s) in RCA: 154] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 06/15/2022] [Accepted: 08/04/2022] [Indexed: 01/26/2023]
Abstract
How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal-specific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders.
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Affiliation(s)
- Yoshinaga Kawano
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Madeline Edwards
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Yiming Huang
- Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Angelina M Bilate
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Leandro P Araujo
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Takeshi Tanoue
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Koji Atarashi
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Mark S Ladinsky
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Steven L Reiner
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Harris H Wang
- Department of Systems Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Daniel Mucida
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA
| | - Kenya Honda
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Ivaylo I Ivanov
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
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12
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Stem Cell Therapy and Innate Lymphoid Cells. Stem Cells Int 2022; 2022:3530520. [PMID: 35958032 PMCID: PMC9363162 DOI: 10.1155/2022/3530520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 11/17/2022] Open
Abstract
Innate lymphoid cells have the capability to communicate with other immune cell types to coordinate the immune system functioning during homeostasis and inflammation. However, these cells behave differently at the functional level, unlike T cells, these cells do not need antigen receptors for activation because they are activated by the interaction of their receptor ligation. In hematopoietic stem cell transplantation (HSCT), T cells and NK cells have been extensively studied but very few studies are available on ILCs. In this review, an attempt has been made to provide current information related to NK and ILCs cell-based stem cell therapies and role of the stem cells in the regulation of ILCs as well. Also, the latest information on the differentiation of NK cells and ILCs from CD34+ hematopoietic stem cells is covered in the article.
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13
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Badrani JH, Strohm AN, Lacasa L, Civello B, Cavagnero K, Haung YA, Amadeo M, Naji LH, Lund SJ, Leng A, Kim H, Baum RE, Khorram N, Mondal M, Seumois G, Pilotte J, Vanderklish PW, McGee HM, Doherty TA. RNA-binding protein RBM3 intrinsically suppresses lung innate lymphoid cell activation and inflammation partially through CysLT1R. Nat Commun 2022; 13:4435. [PMID: 35908044 PMCID: PMC9338970 DOI: 10.1038/s41467-022-32176-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 07/19/2022] [Indexed: 11/09/2022] Open
Abstract
Innate lymphoid cells (ILC) promote lung inflammation in asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators, although less is known about RBPs in ILC biology. Here, we demonstrate that RNA-binding motif 3 (RBM3) is highly expressed in lung ILCs and is further induced by alarmins TSLP and IL-33. Rbm3-/- and Rbm3-/-Rag2-/- mice exposed to asthma-associated Alternaria allergen develop enhanced eosinophilic lung inflammation and ILC activation. IL-33 stimulation studies in vivo and in vitro show that RBM3 suppressed lung ILC responses. Further, Rbm3-/- ILCs from bone marrow chimeric mice display increased ILC cytokine production suggesting an ILC-intrinsic suppressive function of RBM3. RNA-sequencing of Rbm3-/- lung ILCs demonstrates increased expression of type 2/17 cytokines and cysteinyl leukotriene 1 receptor (CysLT1R). Finally, Rbm3-/-Cyslt1r-/- mice show dependence on CysLT1R for accumulation of ST2+IL-17+ ILCs. Thus, RBM3 intrinsically regulates lung ILCs during allergen-induced type 2 inflammation that is partially dependent on CysLT1R.
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Affiliation(s)
- Jana H. Badrani
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Allyssa N. Strohm
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA ,Veterans Affairs San Diego Health Care System, La Jolla, CA USA
| | - Lee Lacasa
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Blake Civello
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Kellen Cavagnero
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Yung-An Haung
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA ,grid.145695.a0000 0004 1798 0922Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Michael Amadeo
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Luay H. Naji
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Sean J. Lund
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Anthea Leng
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Hyojoung Kim
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Rachel E. Baum
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Naseem Khorram
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA
| | - Monalisa Mondal
- grid.185006.a0000 0004 0461 3162La Jolla Institute, La Jolla, CA USA
| | - Grégory Seumois
- grid.185006.a0000 0004 0461 3162La Jolla Institute, La Jolla, CA USA
| | - Julie Pilotte
- grid.214007.00000000122199231The Scripps Research Institute, La Jolla, CA USA
| | | | - Heather M. McGee
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA ,grid.250671.70000 0001 0662 7144NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute, La Jolla, CA USA ,grid.410425.60000 0004 0421 8357Departments of Radiation Oncology and Immuno-Oncology, City of Hope, Duarte, CA USA ,Department of Molecular Medicine, La Jolla, CA USA
| | - Taylor A. Doherty
- grid.266100.30000 0001 2107 4242Divison of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, CA USA ,Veterans Affairs San Diego Health Care System, La Jolla, CA USA
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14
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Ham J, Kim J, Ko YG, Kim HY. The Dynamic Contribution of Neutrophils in the Chronic Respiratory Diseases. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2022; 14:361-378. [PMID: 35837821 PMCID: PMC9293600 DOI: 10.4168/aair.2022.14.4.361] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/21/2022] [Accepted: 06/21/2022] [Indexed: 01/13/2023]
Abstract
Asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis are representative chronic respiratory diseases (CRDs). Although they differ in terms of disease presentation, they are all thought to arise from unresolved inflammation. Neutrophils are not only the first responders to acute inflammation, but they also help resolve the inflammation. Notably, emerging clinical studies show that CRDs are associated with systemic and local elevation of neutrophils. Moreover, murine studies suggest that airway-infiltrating neutrophils not only help initiate airway inflammation but also prolong the inflammation. Given this background, this review describes neutrophil-mediated immune responses in CRDs and summarizes the completed, ongoing, and potential clinical trials that test the therapeutic value of targeting neutrophils in CRDs. The review also clarifies the importance of understanding how neutrophils interact with other immune cells and how these interactions contribute to chronic inflammation in specific CRDs. This information may help identify future therapeutic strategies for CRDs.
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Affiliation(s)
- Jongho Ham
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Department of Biomedical Sciences, BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul, Korea.,CIRNO, Sungkyunkwan University, Suwon, Korea
| | - Jihyun Kim
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
| | - Young Gyun Ko
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Department of Biomedical Sciences, BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul, Korea.,CIRNO, Sungkyunkwan University, Suwon, Korea
| | - Hye Young Kim
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Department of Biomedical Sciences, BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul, Korea.,CIRNO, Sungkyunkwan University, Suwon, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.
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15
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Yamamoto Y, Yoshizawa K, Takamoto M, Soejima Y, Sanjo H, Taki S. Circulating T cells and resident non-T cells restrict type 2 innate lymphoid cell expansion in the small intestine. Biochem Biophys Res Commun 2022; 618:93-99. [PMID: 35716601 DOI: 10.1016/j.bbrc.2022.06.007] [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: 05/17/2022] [Accepted: 06/03/2022] [Indexed: 11/02/2022]
Abstract
Interaction among various adaptive, circulating cells and tissue-resident cells including innate lymphocytes during the establishment and maintenance of the barrier-tissue immune system has only recently started to be explored. Here, we show that the cellular crosstalk with circulating T cells and other resident cells regulated the population size of type 2 innate lymphoid cells (ILC2s) in the small intestine lamina propria. Rag1-/- mice had excessive numbers of both ILC2s and ILC3s, and such an over-expansion was corrected by establishing parabiosis with wild type mice or by adoptively transferring wild type CD4+ T cells. In contrast, anti-CD3 antibody-mediated T cell depletion in wild type mice increased ILC2 but not ILC3 numbers. Unconventional CD4-CD8- αβ T and γδ T cells could also restrict ILC2 expansion as the numbers of ILC2s were not altered even in mice treated with anti-CD4/anti-CD8 antibodies. ILC3 restriction seemed to be through the control of proliferation, but that for ILC2s did not. In addition, elevation in ILC2 numbers seen in mice lacking the transcription factors RORγt and STAT6 was found to be T cell-independent. Our current findings altogether uncovered the homeostatic 'quota' restriction imposed on intestinal ILC2s in the steady state by resident non-T cells via RORγt- and STAT6-dependent mechanisms as well as by conventional and nonconventional T cells.
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Affiliation(s)
- Yuta Yamamoto
- Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan; Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan
| | - Kazuki Yoshizawa
- Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan; Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan
| | - Masaya Takamoto
- Department of Infection and Host Defense, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan
| | - Yuji Soejima
- Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan
| | - Hideki Sanjo
- Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan
| | - Shinsuke Taki
- Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
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16
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Wu X, Gu B, Yang H. The role of γδ T cells in the interaction between commensal and pathogenic bacteria in the intestinal mucosa. Int Rev Immunol 2022; 42:379-392. [PMID: 35583374 DOI: 10.1080/08830185.2022.2076846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/03/2022] [Accepted: 05/06/2022] [Indexed: 12/22/2022]
Abstract
The intestinal mucosa is an important structure involved in resistance to pathogen infection. It is mainly composed of four barriers, which have different but interrelated functions. Pathogenic bacteria can damage these intestinal mucosal barriers. Here, we mainly review the mechanisms of pathogen damage to biological barriers. Most γδ T cells are located on the surface of the intestinal mucosa, with the ability to migrate and engage in crosstalk with microorganisms. Commensal bacteria are involved in the activation and migration of γδ T cells to monitor the invasion of pathogens. Pathogen invasion alters the migration pattern of γδ T cells. γδ T cells accelerate pathogen clearance and limit opportunistic invasion of commensal bacteria. By discussing these interactions among γδ T cells, commensal bacteria and pathogenic bacteria, we suggest that γδ T cells may link the interactions between commensal bacteria and pathogenic bacteria.
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Affiliation(s)
- Xiaoxiao Wu
- Xuzhou Key Laboratory of Laboratory Diagnostics, School of Medical Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Bing Gu
- Xuzhou Key Laboratory of Laboratory Diagnostics, School of Medical Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Laboratory Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Huan Yang
- Xuzhou Key Laboratory of Laboratory Diagnostics, School of Medical Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China
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17
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Gürbüz M, Aktaç Ş. Understanding the role of vitamin A and its precursors in the immune system. NUTR CLIN METAB 2022. [DOI: 10.1016/j.nupar.2021.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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18
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Pope RL, Chitrakar A, Sah P, Shadid T, Ballard JD, Zenewicz LA. Clostridioides difficile Toxin B Activates Group 3 Innate Lymphocytes. Infect Immun 2022; 90:e0007322. [PMID: 35377172 PMCID: PMC9022501 DOI: 10.1128/iai.00073-22] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/05/2022] [Indexed: 11/20/2022] Open
Abstract
Group 3 innate lymphocytes (ILC3s) are rare immune cells localized in mucosal tissues, especially the gastrointestinal (GI) tract. Despite their rarity, they are a major source of the cytokine interleukin-22 (IL-22), which protects the GI epithelium during inflammation and infection. Although ILC3s have been demonstrated to be important for defense against Clostridioides difficile infection, the exact mechanisms through which they sense productive infection and become activated to produce IL-22 remain poorly understood. In this study, we identified a novel mechanism of ILC3 activation after exposure to C. difficile. Toxin B (TcdB) from C. difficile directly induced production of IL-22 in ILC3s, and this induction was dependent on the glucosyltransferase activity of the toxin, which inhibits small GTPases. Pharmacological inhibition of the small GTPase Cdc42 also enhanced IL-22 production in ILC3s, indicating that Cdc42 is a negative regulator of ILC3 activation. Further gene expression analysis revealed that treatment with TcdB modulated the expression of several inflammation-related genes in ILC3s. These findings demonstrate that C. difficile toxin-mediated inhibition of Cdc42 leads to the activation of ILC3s, providing evidence for how these cells are recruited into the immune response against the pathobiont.
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Affiliation(s)
- Rosemary L. Pope
- Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Alisha Chitrakar
- Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Prakash Sah
- Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Tyler Shadid
- Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Jimmy D. Ballard
- Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Lauren A. Zenewicz
- Department of Microbiology and Immunology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
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19
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Barshad G, Webb LM, Ting HA, Oyesola OO, Onyekwere OG, Lewis JJ, Rice EJ, Matheson MK, Sun XH, von Moltke J, Danko CG, Tait Wojno ED. E-Protein Inhibition in ILC2 Development Shapes the Function of Mature ILC2s during Allergic Airway Inflammation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1007-1020. [PMID: 35181641 PMCID: PMC8881320 DOI: 10.4049/jimmunol.2100414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 12/09/2021] [Indexed: 01/16/2023]
Abstract
E-protein transcription factors limit group 2 innate lymphoid cell (ILC2) development while promoting T cell differentiation from common lymphoid progenitors. Inhibitors of DNA binding (ID) proteins block E-protein DNA binding in common lymphoid progenitors to allow ILC2 development. However, whether E-proteins influence ILC2 function upon maturity and activation remains unclear. Mice that overexpress ID1 under control of the thymus-restricted proximal Lck promoter (ID1tg/WT) have a large pool of primarily thymus-derived ILC2s in the periphery that develop in the absence of E-protein activity. We used these mice to investigate how the absence of E-protein activity affects ILC2 function and the genomic landscape in response to house dust mite (HDM) allergens. ID1tg/WT mice had increased KLRG1- ILC2s in the lung compared with wild-type (WT; ID1WT/WT) mice in response to HDM, but ID1tg/WT ILC2s had an impaired capacity to produce type 2 cytokines. Analysis of WT ILC2 accessible chromatin suggested that AP-1 and C/EBP transcription factors but not E-proteins were associated with ILC2 inflammatory gene programs. Instead, E-protein binding sites were enriched at functional genes in ILC2s during development that were later dynamically regulated in allergic lung inflammation, including genes that control ILC2 response to cytokines and interactions with T cells. Finally, ILC2s from ID1tg/WT compared with WT mice had fewer regions of open chromatin near functional genes that were enriched for AP-1 factor binding sites following HDM treatment. These data show that E-proteins shape the chromatin landscape during ILC2 development to dictate the functional capacity of mature ILC2s during allergic inflammation in the lung.
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Affiliation(s)
- Gilad Barshad
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY
- Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY
| | - Lauren M Webb
- Department of Immunology, University of Washington, Seattle, WA;
| | - Hung-An Ting
- Department of Immunology, University of Washington, Seattle, WA
| | | | - Oluomachi G Onyekwere
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY
- Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY; and
| | - James J Lewis
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY
- Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY
| | - Edward J Rice
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY
- Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY
| | - Macy K Matheson
- Department of Immunology, University of Washington, Seattle, WA
| | - Xiao-Hong Sun
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
| | | | - Charles G Danko
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY
- Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY
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20
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He J, Jiang G, Li X, Xiao Q, Chen Y, Xu H, Liu G, Lei A, Zhou P, Shi K, Yang Q, Zhao M, Yao Z, Zhou J. Bilirubin represents a negative regulator of ILC2 in allergic airway inflammation. Mucosal Immunol 2022; 15:314-326. [PMID: 34686839 DOI: 10.1038/s41385-021-00460-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 08/29/2021] [Accepted: 09/16/2021] [Indexed: 02/04/2023]
Abstract
Group 2 innate lymphoid cells (ILC2s) play an important role in allergic airway inflammation. Despite recent advances in defining molecular mechanisms that control ILC2 development and function, the role of endogenous metabolites in the regulation of ILC2s remains poorly understood. Herein, we demonstrated that bilirubin, an end product of heme catabolism, was a potent negative regulator of ILC2s. Bilirubin metabolism was found to be significantly induced during airway inflammation in mouse models. The administration of unconjugated bilirubin (UCB) dramatically suppressed ILC2 responses to interleukin (IL)-33 in mice, including cell proliferation and the production of effector cytokines. Furthermore, UCB significantly alleviated ILC2-driven airway inflammation, which was aggravated upon clearance of endogenous UCB. Mechanistic studies showed that the effects of bilirubin on ILC2s were associated with downregulation of ERK phosphorylation and GATA3 expression. Clinically, newborns with hyperbilirubinemia displayed significantly lower levels of ILC2 with impaired function and suppressed ERK signaling. Together, these findings indicate that bilirubin serves as an endogenous suppressor of ILC2s and might have potential therapeutic value in the treatment of allergic airway inflammation.
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Affiliation(s)
- Juan He
- Joint Program in Immunology, Department of Internal Medicine, Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Guanmin Jiang
- Department of Clinical laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Xing Li
- The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiang Xiao
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Department of Clinical laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Yingying Chen
- Joint Program in Immunology, Department of Internal Medicine, Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Haixu Xu
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Gaoyu Liu
- Joint Program in Immunology, Department of Internal Medicine, Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Aihua Lei
- Joint Program in Immunology, Department of Internal Medicine, Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Pan Zhou
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Kun Shi
- Department of Obstetrics and Gynaecology, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Quan Yang
- Key Laboratory of Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences; Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Meng Zhao
- Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhi Yao
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
| | - Jie Zhou
- Joint Program in Immunology, Department of Internal Medicine, Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
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21
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Jagadeesan S, Dhar S. Atopic March: Dermatologic perspectives. Indian J Dermatol 2022; 67:265-272. [PMID: 36386083 PMCID: PMC9644798 DOI: 10.4103/ijd.ijd_989_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The progression of allergic diseases with the development of atopic dermatitis and food allergy in infancy and subsequent asthma and allergic rhinitis in the later childhood is known as 'atopic march'. There have been many arguments in favour of and against this concept. This article reviews the latest epidemiology, immunological mechanisms and translational implications in clinical practice and research, which is relevant to the dermatologists. The role of skin as a site of initiation and the potential for interventions on skin that may prevent subsequent allergic diseases is also highlighted.
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22
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Portincasa P, Bonfrate L, Khalil M, Angelis MD, Calabrese FM, D’Amato M, Wang DQH, Di Ciaula A. Intestinal Barrier and Permeability in Health, Obesity and NAFLD. Biomedicines 2021; 10:83. [PMID: 35052763 PMCID: PMC8773010 DOI: 10.3390/biomedicines10010083] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/20/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Francesco Maria Calabrese
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Mauro D’Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE-BRTA, 48160 Derio, Spain;
- Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
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Yan J, Yu J, Liu K, Liu Y, Mao C, Gao W. The Pathogenic Roles of IL-22 in Colitis: Its Transcription Regulation by Musculin in T Helper Subsets and Innate Lymphoid Cells. Front Immunol 2021; 12:758730. [PMID: 34992594 PMCID: PMC8724035 DOI: 10.3389/fimmu.2021.758730] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 12/06/2021] [Indexed: 12/12/2022] Open
Abstract
IL-22 plays a crucial role in promoting inflammation, antimicrobial immunity and tissue repair at barrier surfaces. The role of IL-22 in colitis is still controversial: while IL-22 has a protective effect on gut epithelium in acute injuries, it also enhances colitis in a context-dependent manner. Here, we summarize the Yin and Yang of IL-22 in colitis. Particularly, we emphasize the role of innate lymphoid cells (ILCs) in IL-22 production and regulation. A previously underappreciated transcription factor, Musculin (MSC), has been recently identified to be expressed in not only Th17 cells, but also RORγt+/Id2+ IL-22-producing group 3 ILCs in the gut of naïve mice. We hypothesize that the co-expression and interaction of MSC with the key transcription repressor Id2 in developing lymphoid cells (e.g., in LTi cells) and ILC precursors might fine tune the developmental programs or regulate the plasticity of adaptive Th subset and innate ILCs. The much-elevated expression of IL-22 in MSC-/- ILC3s suggests that MSC may function as: 1) a transcription suppressor for cytokines, particularly for IL-22, and/or 2) a gatekeeper for specific lineages of Th cells and innate ILCs as well. Amelioration of colitis symptoms in MSC-/- mice by IL-22-blocking agent IL-22BP-Fc suggests a counterintuitive pathogenic role of IL-22 in the absence of MSC as a checkpoint. The theory that exuberant production of IL-22 under pathological conditions (e.g., in human inflammatory bowel disease, IBD) may cause epithelial inflammation due to endoplasmic reticulum (ER) stress response is worth further investigation. Rheostatic regulation of IL-22 may be of therapeutic value to restore homeostatic balance and promote intestinal health in human colitis.
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Affiliation(s)
- Jun Yan
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Special War Wound, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jing Yu
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Special War Wound, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Ke Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Special War Wound, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Yijia Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Special War Wound, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | | | - Wenda Gao
- Antagen Pharmaceuticals, Boston, MA, United States
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Liu C, Gong Y, Zhang H, Yang H, Zeng Y, Bian Z, Xin Q, Bai Z, Zhang M, He J, Yan J, Zhou J, Li Z, Ni Y, Wen A, Lan Y, Hu H, Liu B. Delineating spatiotemporal and hierarchical development of human fetal innate lymphoid cells. Cell Res 2021; 31:1106-1122. [PMID: 34239074 PMCID: PMC8486758 DOI: 10.1038/s41422-021-00529-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/08/2021] [Indexed: 02/07/2023] Open
Abstract
Whereas the critical roles of innate lymphoid cells (ILCs) in adult are increasingly appreciated, their developmental hierarchy in early human fetus remains largely elusive. In this study, we sorted human hematopoietic stem/progenitor cells, lymphoid progenitors, putative ILC progenitor/precursors and mature ILCs in the fetal hematopoietic, lymphoid and non-lymphoid tissues, from 8 to 12 post-conception weeks, for single-cell RNA-sequencing, followed by computational analysis and functional validation at bulk and single-cell levels. We delineated the early phase of ILC lineage commitment from hematopoietic stem/progenitor cells, which mainly occurred in fetal liver and intestine. We further unveiled interleukin-3 receptor as a surface marker for the lymphoid progenitors in fetal liver with T, B, ILC and myeloid potentials, while IL-3RA- lymphoid progenitors were predominantly B-lineage committed. Notably, we determined the heterogeneity and tissue distribution of each ILC subpopulation, revealing the proliferating characteristics shared by the precursors of each ILC subtype. Additionally, a novel unconventional ILC2 subpopulation (CRTH2- CCR9+ ILC2) was identified in fetal thymus. Taken together, our study illuminates the precise cellular and molecular features underlying the stepwise formation of human fetal ILC hierarchy with remarkable spatiotemporal heterogeneity.
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Affiliation(s)
- Chen Liu
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China
| | - Yandong Gong
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Han Zhang
- Department of Blood Transfusion, Daping Hospital, Army Military Medical University, Chongqing, China
| | - Hua Yang
- Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China
| | - Yang Zeng
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhilei Bian
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Qian Xin
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China
| | - Zhijie Bai
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China
| | - Man Zhang
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China
| | - Jian He
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China
| | - Jing Yan
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China
| | - Jie Zhou
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zongcheng Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yanli Ni
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Aiqing Wen
- Department of Blood Transfusion, Daping Hospital, Army Military Medical University, Chongqing, China.
| | - Yu Lan
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China.
| | - Hongbo Hu
- Center for Immunology and Hematology, the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University. Collaboration and Innovation Center for Biotherapy, Chengdu, China.
| | - Bing Liu
- State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, China.
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China.
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25
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Abstract
PURPOSE OF REVIEW To perform a nonsystematic review of the literature on the possible role of probiotics for food allergy (FA). RECENT FINDINGS Animal model and in vitro evidence suggest that the gut microbiome could protect against FA and that probiotics could be a valid instrument. There is no consistent evidence in identifying the specific species, the dosage, and the optimal duration to obtain the correct immunomodulation. Early life supplementation with specific 'missing' immunomodulatory microbes - derived from machine learning approach to birth cohort studies - might represent a novel approach to the primary prevention of multiple human atopic diseases. However, further studies are needed. SUMMARY Currently, there is no positive recommendation from the main scientific societies to use probiotics neither for the treatment nor for the prevention of FA.
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Affiliation(s)
- Maurizio Mennini
- Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
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26
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Zhou CB, Zhou YL, Fang JY. Gut Microbiota in Cancer Immune Response and Immunotherapy. Trends Cancer 2021; 7:647-660. [PMID: 33674230 DOI: 10.1016/j.trecan.2021.01.010] [Citation(s) in RCA: 175] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 12/17/2022]
Abstract
The gastrointestinal tract (GIT) is the largest immune organ and maintains systemic immune homeostasis in the presence of bacterial challenge. Immune elimination and immune escape are hallmarks of cancer, both of which can be partly bacteria dependent in shaping immunity by mediating host immunomodulation. In addition, host immunity regulates the microbiome by altering bacteria-associated signaling to influence tumor surveillance. Cancer immunotherapy, including immune checkpoint blockade (ICB), appears to have heterogeneous therapeutic effects in different individuals, partially attributed to the microbiota. Thus, the microbiome signature can predict clinical outcomes, prognosis, and immunotherapy responses. In this review, we summarize the intricate crosstalk among the gut microbiome, cancer immune response, and immunotherapy. Interactive modulation of the host microbiota provides new therapeutic strategies to promote anticancer therapy efficacy and/or reduce toxicity.
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Affiliation(s)
- Cheng-Bei Zhou
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai, China
| | - Yi-Lu Zhou
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai, China
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, 145 Middle Shandong Road, Shanghai, China.
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27
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Gut Microbiota-Host Interactions in Inborn Errors of Immunity. Int J Mol Sci 2021; 22:ijms22031416. [PMID: 33572538 PMCID: PMC7866830 DOI: 10.3390/ijms22031416] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 12/11/2022] Open
Abstract
Inborn errors of immunity (IEI) are a group of disorders that are mostly caused by genetic mutations affecting immune host defense and immune regulation. Although IEI present with a wide spectrum of clinical features, in about one third of them various degrees of gastrointestinal (GI) involvement have been described and for some IEI the GI manifestations represent the main and peculiar clinical feature. The microbiome plays critical roles in the education and function of the host's innate and adaptive immune system, and imbalances in microbiota-immunity interactions can contribute to intestinal pathogenesis. Microbial dysbiosis combined to the impairment of immunosurveillance and immune dysfunction in IEI, may favor mucosal permeability and lead to inflammation. Here we review how immune homeostasis between commensals and the host is established in the gut, and how these mechanisms can be disrupted in the context of primary immunodeficiencies. Additionally, we highlight key aspects of the first studies on gut microbiome in patients affected by IEI and discuss how gut microbiome could be harnessed as a therapeutic approach in these diseases.
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28
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Impact of a Demyelination-Inducing Central Nervous System Virus on Expression of Demyelination Genes in Type 2 Lymphoid Cells. J Virol 2021; 95:JVI.01934-20. [PMID: 33208451 DOI: 10.1128/jvi.01934-20] [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: 09/28/2020] [Accepted: 11/12/2020] [Indexed: 11/20/2022] Open
Abstract
We recently reported the role of type 2 innate lymphoid cells (ILC2s) in central nervous system (CNS) demyelination using a model of CNS demyelination involving recombinant herpes simplex virus 1 (HSV-1) that constitutively expresses mouse interleukin 2 (HSV-IL-2). In this investigation, we studied how ILC2s respond to HSV-IL-2 at the cellular level using cytokine and gene expression profiling. ILC2s infected with HSV-IL-2 expressed higher levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, IL-6, IL-13, IP-10, MIP-2, and RANTES, which include proinflammatory cytokines, than did those infected with parental control virus. In contrast, TH2 cytokines IL-4 and IL-9, which are typically expressed by ILC2s, were not induced upon HSV-IL-2 infection. Transcriptome sequencing (RNA-seq) analysis of HSV-IL-2 infected ILC2s showed significant upregulation of over 350 genes and downregulation of 157 genes compared with parental virus-infected ILC2s. Gene Ontology (GO) term analysis indicated that genes related to "mitosis" and "inflammatory response" were among the upregulated genes, suggesting that HSV-IL-2 infection drives the excessive proliferation and atypical inflammatory response of ILC2s. This change in ILC2 activation state could underlie the pathology of demyelinating diseases.IMPORTANCE Innate lymphocytes have plasticity and can change functionality; type 2 innate lymphoid cells (ILC2s) can convert to ILC1 or ILC3 cells or change their activation state to produce IL-17 or IL-10 depending on environmental cues. In this study, we investigated the gene and cytokine profiles of ILC2s, which play a major role in HSV-IL-2-induced CNS demyelination. ILC2s infected with HSV-IL-2 displayed a massive remodeling of cellular state. Additionally, ILC2s infected with HSV-IL-2 differed from those infected with parental HSV in cellular and viral gene expression profiles and in cytokine/chemokine induction, and they displayed enhanced activation and proinflammatory responses. These changes in ILC2 activation state could underlie the pathology of demyelinating diseases. These results also highlight the possible importance of pathogens as environmental cues to modify innate lymphocyte functionalities.
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REIS BPZCD, ORGE ID, SAMPAIO GLDA, DALTRO SRT, SANTOS RRD, MEIRA CS, SOARES MBP. Mesenchymal Stem cells in the context of canine atopic dermatitis: A Review. REVISTA BRASILEIRA DE SAÚDE E PRODUÇÃO ANIMAL 2021. [DOI: 10.1590/s1519-99402122242021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
ABSTRACT Canine atopic dermatitis (CAD) is a chronic inflammatory skin disease and has a high frequency among dermatological diseases. The interaction of genetic factors, skin and environmental conditions affect the expression of the disease, developing a complex pathology. Current multimodal treatment has numerous adverse effects and variations in its efficacy and safety, demonstrating the need to develop safe and effective therapeutic resources for patients with CAD. Mesenchymal stem cells (MSCs) are multipotent cells, with special characteristics, such as self-renewal, immunomodulatory properties, and de-differentiation, making them useful for several clinical problems. The discovery of the immunosuppressive effect of MSCs on T cells has opened the potential for new perspectives with its use as a therapeutic agent for immune diseases, such as CAD. The scarce number of research using the MSC as a treatment for CAD result in the lack of knowledge about the benefits and possible protocols to be followed for the use of this cell therapy. In this review, we highlighted the clinical studies and potential biological mechanisms of MSC-based cell therapy effects attenuating canine atopic dermatitis compared to conventional treatment, which might lead to a safe improvement of the animal’s clinical condition in a short period without causing adverse effects.
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Affiliation(s)
| | | | | | | | | | - Cássio Santana MEIRA
- Oswaldo Cruz Foundation (FIOCRUZ), Brazil; University Center SENAI/CIMATEC, Brazil
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30
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Kable ME, Riazati N, Kirschke CP, Zhao J, Tepaamorndech S, Huang L. The Znt7-null mutation has sex dependent effects on the gut microbiota and goblet cell population in the mouse colon. PLoS One 2020; 15:e0239681. [PMID: 32991615 PMCID: PMC7523961 DOI: 10.1371/journal.pone.0239681] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/11/2020] [Indexed: 01/01/2023] Open
Abstract
Cellular homeostasis of zinc, an essential element for living organisms, is tightly regulated by a family of zinc transporters. The zinc transporter 7, ZnT7, is highly expressed on the membrane of the Golgi complex of intestinal epithelial cells and goblet cells. It has previously been shown that Znt7 knockout leads to zinc deficiency and decreased weight gain in C57BL/6 mice on a defined diet. However, effects within the colon are unknown. Given the expression profile of Znt7, we set out to analyze the changes in mucin density and gut microbial composition in the mouse large intestine induced by Znt7 knockout. We fed a semi-purified diet containing 30 mg Zn/kg to Znt7-/- mice with their heterozygous and wild type littermates and found a sex specific effect on colonic mucin density, goblet cell number, and microbiome composition. In male mice Znt7 knockout led to increased goblet cell number and mucin density but had little effect on gut microbiome composition. However, in female mice Znt7 knockout was associated with decreased goblet cell number and mucin density, with increased proportions of the microbial taxa, Allobaculum, relative to wild type. The gut microbial composition was correlated with mucin density in both sexes. These findings suggest that a sex-specific relationship exists between zinc homeostasis, mucin production and the microbial community composition within the colon.
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Affiliation(s)
- Mary E. Kable
- Immunity and Disease Prevention Research Unit, USDA-ARS, Western Human Nutrition Research Center, Davis, California, United States of America
- Department of Nutrition, University of California Davis, Davis, California, United States of America
- * E-mail: (MEK); (LH)
| | - Niknaz Riazati
- Department of Nutrition, University of California Davis, Davis, California, United States of America
| | - Catherine P. Kirschke
- Obesity and Metabolism Research Unit, USDA-ARS, Western Human Nutrition Research Center, Davis, California, United States of America
| | - Junli Zhao
- School of Food Science, Nanjing Xiaozhuang University, Nanjing, Jiangsu, China
| | - Surapun Tepaamorndech
- Food Biotechnology Research Unit, National Center for Genetic Engineering and Biotechnology (BIOTEC), Khlong Luang, Pathum Thani, Thailand
| | - Liping Huang
- Department of Nutrition, University of California Davis, Davis, California, United States of America
- Obesity and Metabolism Research Unit, USDA-ARS, Western Human Nutrition Research Center, Davis, California, United States of America
- * E-mail: (MEK); (LH)
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Hirose S, Jahani PS, Wang S, Jaggi U, Tormanen K, Yu J, Kato M, Akbari O, Ghiasi H. Type 2 Innate Lymphoid Cells Induce CNS Demyelination in an HSV-IL-2 Mouse Model of Multiple Sclerosis. iScience 2020; 23:101549. [PMID: 33083718 PMCID: PMC7522755 DOI: 10.1016/j.isci.2020.101549] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/24/2020] [Accepted: 09/07/2020] [Indexed: 02/06/2023] Open
Abstract
We previously reported that infection of different mouse strains with a recombinant HSV-1 expressing IL-2 (HSV-IL-2) caused CNS demyelination. Histologic examination of infected IL-2rα-/-, IL-2rβ-/-, and IL-2rγ-/- mice showed demyelination in the CNS of IL-2rα-/- and IL-2rβ-/- mice but not in the CNS of IL-2rγ-/--infected mice. No demyelination was detected in mice infected with control virus. IL-2rγ-/- mice that lack type 2 innate lymphoid cells (ILC2s) and ILCs, play important roles in host defense and inflammation. We next infected ILC1-/-, ILC2-/-, and ILC3-/- mice with HSV-IL-2 or wild-type (WT) HSV-1. In contrast to ILC1-/- and ILC3-/- mice, no demyelination was detected in the CNS of ILC2-/--sinfected mice. However, transfer of ILC2s from WT mice to ILC2-/- mice restored demyelination in infected recipient mice. CNS demyelination correlated with downregulation of CCL5 and CXCL10. This study demonstrates that ILC2s contribute to HSV-IL-2-induced CNS demyelination in a mouse model of multiple sclerosis.
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Affiliation(s)
- Satoshi Hirose
- Department of Surgery, Center for Neurobiology and Vaccine Development, Ophthalmology Research, Cedars-Sinai Medical Center, SSB3, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
| | - Pedram Shafiei Jahani
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Shaohui Wang
- Department of Surgery, Center for Neurobiology and Vaccine Development, Ophthalmology Research, Cedars-Sinai Medical Center, SSB3, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
| | - Ujjaldeep Jaggi
- Department of Surgery, Center for Neurobiology and Vaccine Development, Ophthalmology Research, Cedars-Sinai Medical Center, SSB3, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
| | - Kati Tormanen
- Department of Surgery, Center for Neurobiology and Vaccine Development, Ophthalmology Research, Cedars-Sinai Medical Center, SSB3, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
| | - Jack Yu
- Department of Surgery, Center for Neurobiology and Vaccine Development, Ophthalmology Research, Cedars-Sinai Medical Center, SSB3, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
| | - Mihoko Kato
- Department of Biology, Pomona College, Claremont, CA, USA
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Homayon Ghiasi
- Department of Surgery, Center for Neurobiology and Vaccine Development, Ophthalmology Research, Cedars-Sinai Medical Center, SSB3, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
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32
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Grondin JA, Kwon YH, Far PM, Haq S, Khan WI. Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies. Front Immunol 2020; 11:2054. [PMID: 33013869 PMCID: PMC7500085 DOI: 10.3389/fimmu.2020.02054] [Citation(s) in RCA: 252] [Impact Index Per Article: 50.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/28/2020] [Indexed: 12/24/2022] Open
Abstract
Throughout the gastrointestinal (GI) tract, a distinct mucus layer composed of highly glycosylated proteins called mucins plays an essential role in providing lubrication for the passage of food, participating in cell signaling pathways and protecting the host epithelium from commensal microorganisms and invading pathogens, as well as toxins and other environmental irritants. These mucins can be broadly classified into either secreted gel-forming mucins, those that provide the structural backbone for the mucus barrier, or transmembrane mucins, those that form the glycocalyx layer covering the underlying epithelial cells. Goblet cells dispersed among the intestinal epithelial cells are chiefly responsible for the synthesis and secretion of mucins within the gut and are heavily influenced by interactions with the immune system. Evidence from both clinical and animal studies have indicated that several GI conditions, including inflammatory bowel disease (IBD), colorectal cancer, and numerous enteric infections are accompanied by considerable changes in mucin quality and quantity. These changes include, but are not limited to, impaired goblet cell function, synthesis dysregulation, and altered post-translational modifications. The current review aims to highlight the structural and functional features as well as the production and immunological regulation of mucins and the impact these key elements have within the context of barrier function and host defense in intestinal inflammation.
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Affiliation(s)
- Jensine A Grondin
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Yun Han Kwon
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Parsa Mehraban Far
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Sabah Haq
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
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Oyesola OO, Früh SP, Webb LM, Tait Wojno ED. Cytokines and beyond: Regulation of innate immune responses during helminth infection. Cytokine 2020; 133:154527. [PMID: 30241895 PMCID: PMC6422760 DOI: 10.1016/j.cyto.2018.08.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 08/18/2018] [Accepted: 08/20/2018] [Indexed: 12/22/2022]
Abstract
Parasitic helminth infection elicits a type 2 cytokine-mediated inflammatory response. During type 2 inflammation, damaged or stimulated epithelial cells exposed to helminths and their products produce alarmins and cytokines including IL-25, IL-33, and thymic stromal lymphopoietin. These factors promote innate immune cell activation that supports the polarization of CD4+ T helper type 2 (Th2) cells. Activated innate and Th2 cells produce the cytokines IL-4, -5, -9, and -13 that perpetuate immune activation and act back on the epithelium to cause goblet cell hyperplasia and increased epithelial cell turnover. Together, these events facilitate worm expulsion and wound healing processes. While the role of Th2 cells in this context has been heavily studied, recent work has revealed that epithelial cell-derived cytokines are drivers of key innate immune responses that are critical for type 2 anti-helminth responses. Cutting-edge studies have begun to fully assess how other factors and pathways, including lipid mediators, chemokines, Fc receptor signaling, danger-associated molecular pattern molecules, and direct cell-cell interactions, also participate in shaping innate cell-mediated type 2 inflammation. In this review, we discuss how these pathways intersect and synergize with pathways controlled by epithelial cell-derived cytokines to coordinate innate immune responses that drive helminth-induced type 2 inflammation.
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Affiliation(s)
- Oyebola O Oyesola
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Simon P Früh
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Lauren M Webb
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Elia D Tait Wojno
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA.
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Di Ciaula A, Baj J, Garruti G, Celano G, De Angelis M, Wang HH, Di Palo DM, Bonfrate L, Wang DQH, Portincasa P. Liver Steatosis, Gut-Liver Axis, Microbiome and Environmental Factors. A Never-Ending Bidirectional Cross-Talk. J Clin Med 2020; 9:2648. [PMID: 32823983 PMCID: PMC7465294 DOI: 10.3390/jcm9082648] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/07/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and parallels comorbidities such as obesity, metabolic syndrome, dyslipidemia, and diabetes. Recent studies describe the presence of NAFLD in non-obese individuals, with mechanisms partially independent from excessive caloric intake. Increasing evidences, in particular, point towards a close interaction between dietary and environmental factors (including food contaminants), gut, blood flow, and liver metabolism, with pathways involving intestinal permeability, the composition of gut microbiota, bacterial products, immunity, local, and systemic inflammation. These factors play a critical role in the maintenance of intestinal, liver, and metabolic homeostasis. An anomalous or imbalanced gut microbial composition may favor an increased intestinal permeability, predisposing to portal translocation of microorganisms, microbial products, and cell wall components. These components form microbial-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs), with potentials to interact in the intestine lamina propria enriched in immune cells, and in the liver at the level of the immune cells, i.e., Kupffer cells and stellate cells. The resulting inflammatory environment ultimately leads to liver fibrosis with potentials to progression towards necrotic and fibrotic changes, cirrhosis. and hepatocellular carcinoma. By contrast, measures able to modulate the composition of gut microbiota and to preserve gut vascular barrier might prevent or reverse NAFLD.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Giuseppe Celano
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (G.C.); (M.D.A.)
| | - Maria De Angelis
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (G.C.); (M.D.A.)
| | - Helen H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.H.W.); (D.Q.-H.W.)
| | - Domenica Maria Di Palo
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (G.C.); (M.D.A.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
| | - David Q-H Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.H.W.); (D.Q.-H.W.)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
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Li Y, Lopez GE, Lindner PN, Parrella L, Larson M, Sun Y, Stanic AK. The role of RORγt at maternal-fetal interface during murine pregnancy. Am J Reprod Immunol 2020; 84:e13250. [PMID: 32314428 PMCID: PMC8261794 DOI: 10.1111/aji.13250] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/15/2020] [Accepted: 04/04/2020] [Indexed: 11/28/2022] Open
Abstract
PROBLEM Innate lymphoid cells (ILCs, including NK cells) and their subsets are the most frequent lymphocytes at the maternal-fetal interface (decidua). Recent recognition of extensive ILC subset diversity at mucosal sites and the possible role they might play at different stages of pregnancy poses questions about their composition and lineage stability. Namely, RORγt-dependent ILC3s have been recognized as a key cellular mediator of tissue organization in the gut and secondary lymphoid organs, prompting examination of their distribution and role in decidua during pregnancy. METHOD OF STUDY We employed highly polychromatic flow cytometry with conventional and machine learning-aided analysis to map ILC subsets and dissected the role of canonical transcription factor RORγt using fate-mapping animals and RORγt-/- animals. RESULTS We demonstrate a comprehensive immunome map of ILCs/NKs, revealing a dynamic interface even in the absence of antigenic or allogeneic challenge. Strikingly, we demonstrate plasticity of RORγt expression in decidual ILCs with across gestation. However, gross reproductive efficiency is not affected in RORγt-/- animals. CONCLUSION These results indicated that RORγt+ ILCs are highly plastic at the maternal-fetal interface, but dispensable for normal pregnancy, revealing a novel mechanism of transcriptional immunoregulation in pregnancy.
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Affiliation(s)
- Yan Li
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Gladys E. Lopez
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Payton N. Lindner
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Luke Parrella
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Mariah Larson
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Yan Sun
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
- Reproductive Medicine Center, Fujian Provincial Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University
| | - Aleksandar K. Stanic
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
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36
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Di Costanzo M, Carucci L, Berni Canani R, Biasucci G. Gut Microbiome Modulation for Preventing and Treating Pediatric Food Allergies. Int J Mol Sci 2020; 21:ijms21155275. [PMID: 32722378 PMCID: PMC7432728 DOI: 10.3390/ijms21155275] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 12/11/2022] Open
Abstract
The increasing prevalence and severity of pediatric food allergies (FA) demands innovative preventive and therapeutic strategies. Emerging evidence suggests a pivotal role for the gut microbiome in modulating susceptibility to FA. Studies have demonstrated that alteration of gut microbiome could precede FA, and that particular microbial community structures early in life could influence also the disease course. The identification of gut microbiome features in pediatric FA patients is driving new prevention and treatment approaches. This review is focused on the potential role of the gut microbiome as a target for FA prevention and treatment.
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Affiliation(s)
- Margherita Di Costanzo
- Department of Pediatrics and Neonatology, Guglielmo da Saliceto Hospital, 29121 Piacenza, Italy;
- Department of Translational Medical Science-Pediatric Section, University “Federico II”, 80131 Naples, Italy; (L.C.); (R.B.C.)
- ImmunoNutritionLab-CEINGE Advanced Biotechnologies, University “Federico II”, 80131 Naples, Italy
- Correspondence:
| | - Laura Carucci
- Department of Translational Medical Science-Pediatric Section, University “Federico II”, 80131 Naples, Italy; (L.C.); (R.B.C.)
- ImmunoNutritionLab-CEINGE Advanced Biotechnologies, University “Federico II”, 80131 Naples, Italy
| | - Roberto Berni Canani
- Department of Translational Medical Science-Pediatric Section, University “Federico II”, 80131 Naples, Italy; (L.C.); (R.B.C.)
- ImmunoNutritionLab-CEINGE Advanced Biotechnologies, University “Federico II”, 80131 Naples, Italy
- Task Force on Microbiome Studies, University of Naples “Federico II”, 80131 Naples, Italy
- European Laboratory for the Investigation of Food-Induced Diseases, University of Naples “Federico II”, 80131 Naples, Italy
| | - Giacomo Biasucci
- Department of Pediatrics and Neonatology, Guglielmo da Saliceto Hospital, 29121 Piacenza, Italy;
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Vazquez J, Chavarria M, Lopez GE, Felder MA, Kapur A, Romo Chavez A, Karst N, Barroilhet L, Patankar MS, Stanic AK. Identification of unique clusters of T, dendritic, and innate lymphoid cells in the peritoneal fluid of ovarian cancer patients. Am J Reprod Immunol 2020; 84:e13284. [PMID: 32524661 DOI: 10.1111/aji.13284] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/09/2020] [Accepted: 06/02/2020] [Indexed: 12/15/2022] Open
Abstract
PROBLEM We hypothesize that activated peritoneal immune cells can be redirected to target ovarian tumors. Here, we obtain fundamental knowledge of the peritoneal immune environment through deep immunophenotyping of T cells, dendritic cells (DC), and innate lymphoid cells (ILC) of ovarian cancer patients. METHOD OF STUDY T cells, DC, and ILC from ascites of ovarian cancer patients (n = 15) and peripheral blood of post-menopausal healthy donors (n = 6) were immunophenotyped on a BD Fortessa cytometer using three panels-each composed of 16 antibodies. The data were analyzed manually and by t-SNE/DensVM. CA125 levels were obtained from patient charts. RESULTS We observed decreased CD3+ T cells and a higher proportion of activated CD4+ and effector memory CD4+ /CD8+ T cells, plasmacytoid DC, CD1c+ and CD141+ myeloid DC and CD56Hi NK cells in ascites. t-SNE/DensVM identified eight T cell, 17 DC, and 17 ILC clusters that were unique in the ascites compared to controls. Hierarchical clustering of cell frequency distinctly segregated the T-cell and ILC clusters from controls. Increased CA125 levels were associated with decreased CD8+ /CD45RA+ /CD45RO- /CCR7- T cells. CONCLUSION The identified immune clusters serve as the basis for interrogation of the peritoneal immune environment and the development of novel immunologic modalities against ovarian cancer.
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Affiliation(s)
- Jessica Vazquez
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Melina Chavarria
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Gladys E Lopez
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Mildred A Felder
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Arvinder Kapur
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Antonio Romo Chavez
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Nathan Karst
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Lisa Barroilhet
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Manish S Patankar
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Aleksandar K Stanic
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
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38
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Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J Hepatol 2020; 72:558-577. [PMID: 31622696 DOI: 10.1016/j.jhep.2019.10.003] [Citation(s) in RCA: 1175] [Impact Index Per Article: 235.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/14/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023]
Abstract
The gut-liver axis refers to the bidirectional relationship between the gut and its microbiota, and the liver, resulting from the integration of signals generated by dietary, genetic and environmental factors. This reciprocal interaction is established by the portal vein which enables transport of gut-derived products directly to the liver, and the liver feedback route of bile and antibody secretion to the intestine. The intestinal mucosal and vascular barrier is the functional and anatomical structure that serves as a playground for the interactions between the gut and the liver, limiting the systemic dissemination of microbes and toxins while allowing nutrients to access the circulation and to reach the liver. The control of microbial communities is critical to maintaining homeostasis of the gut-liver axis, and as part of this bidirectional communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut-liver axis at multiple interconnected levels, including the gut microbiome, mucus barrier, epithelial barrier and at the level of antimicrobial peptide production, which increases microbial exposure and the proinflammatory environment of the liver. Growing evidence indicates the pathogenetic role of microbe-derived metabolites, such as trimethylamine, secondary bile acids, short-chain fatty acids and ethanol, in the pathogenesis of non-alcoholic fatty liver disease. Cirrhosis by itself is associated with profound alterations in gut microbiota and damage at the different levels of defence of the intestinal barrier, including the epithelial, vascular and immune barriers. The relevance of the severe disturbance of the intestinal barrier in cirrhosis has been linked to translocation of live bacteria, bacterial infections and disease progression. The identification of the elements of the gut-liver axis primarily damaged in each chronic liver disease offers possibilities for intervention. Beyond antibiotics, upcoming therapies centred on the gut include new generations of probiotics, bacterial metabolites (postbiotics), faecal microbial transplantation, and carbon nanoparticles. FXR-agonists target both the gut and the liver and are currently being tested in different liver diseases. Finally, synthetic biotic medicines, phages that target specific bacteria or therapies that create physical barriers between the gut and the liver offer new therapeutic approaches.
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Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, IRYCIS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - Andrea de Gottardi
- Hepatology, Inselspital and Department of Biomedical Research, University of Bern, Switzerland; Servizio di Gastroenterología e Epatologia, Ente Ospedaliero Cantonale, Università della Svizzera Italiana, Lugano, Switzerland
| | - María Rescigno
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele (Mi), Italy; Humanitas Clinical and Research Center, IRCCS, 20089 Rozzano (Mi), Italy
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Dery KJ, Kadono K, Hirao H, Górski A, Kupiec-Weglinski JW. Microbiota in organ transplantation: An immunological and therapeutic conundrum? Cell Immunol 2020; 351:104080. [PMID: 32139071 DOI: 10.1016/j.cellimm.2020.104080] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/23/2020] [Accepted: 02/25/2020] [Indexed: 12/15/2022]
Abstract
The gastrointestinal (GI) tract microbiota is an environmental factor that regulates host immunity in allo-transplantation (allo-Tx). It is required for the development of resistance against pathogens and the stabilization of mucosa-associated lymphoid tissue. The gut-microbiota axis may also precipitate allograft rejection by producing metabolites that activate host cell-mediated and humoral immunity. Here, we discuss new insights into microbial immunomodulation, highlighting ongoing attempts to affect commensal colonization in an attempt to ameliorate allograft rejection cascade. Recent progress on the use of antibiotics to modulate GI microbiota diversity and innate-adaptive immune interface are discussed. Our focus on the microbiota's influence of endoplasmic reticulum (ER) stress and autophagy signaling through hepatic EP4/CHOP/LC3B platforms reveals a novel molecular pathway and potential biomarkers determining the progression of allo-Tx damage. Understanding and harnessing the potential of microbiome/bacteriophage therapies may offer safe and effective means for personalized treatment to reduce risks of infections and immunosuppression in allo-Tx.
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Affiliation(s)
- Kenneth J Dery
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles 90095, CA, USA
| | - Kentaro Kadono
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles 90095, CA, USA
| | - Hirofumi Hirao
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles 90095, CA, USA
| | - Andrzej Górski
- Bacteriophage Laboratory and Phage Therapy Unit, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Jerzy W Kupiec-Weglinski
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles 90095, CA, USA.
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40
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Oyesola OO, Duque C, Huang LC, Larson EM, Früh SP, Webb LM, Peng SA, Tait Wojno ED. The Prostaglandin D 2 Receptor CRTH2 Promotes IL-33-Induced ILC2 Accumulation in the Lung. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 204:1001-1011. [PMID: 31900341 PMCID: PMC6994842 DOI: 10.4049/jimmunol.1900745] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 12/05/2019] [Indexed: 12/18/2022]
Abstract
Group 2 innate lymphoid cells (ILC2s) are rare innate immune cells that accumulate in tissues during allergy and helminth infection, performing critical effector functions that drive type 2 inflammation. ILC2s express ST2, the receptor for the cytokine IL-33, and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), a receptor for the bioactive lipid prostaglandin D2 (PGD2). The IL-33-ST2 and the PGD2-CRTH2 pathways have both been implicated in promoting ILC2 accumulation during type 2 inflammation. However, whether these two pathways coordinate to regulate ILC2 population size in the tissue in vivo remains undefined. In this study, we show that ILC2 accumulation in the murine lung in response to systemic IL-33 treatment was partially dependent on CRTH2. This effect was not a result of reduced ILC2 proliferation, increased apoptosis or cell death, or differences in expression of the ST2 receptor in the absence of CRTH2. Rather, data from adoptive transfer studies suggested that defective accumulation of CRTH2-deficient ILC2s in response to IL-33 was due to altered ILC2 migration patterns. Whereas donor wild-type ILC2s preferentially accumulated in the lungs compared with CRTH2-deficient ILC2s following transfer into IL-33-treated recipients, wild-type and CRTH2-deficient ILC2s accumulated equally in the recipient mediastinal lymph node. These data suggest that CRTH2-dependent effects lie downstream of IL-33, directly affecting the migration of ILC2s into inflamed lung tissues. A better understanding of the complex interactions between the IL-33 and PGD2-CRTH2 pathways that regulate ILC2 population size will be useful in understanding how these pathways could be targeted to treat diseases associated with type 2 inflammation.
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MESH Headings
- Adoptive Transfer
- Animals
- Cell Movement/immunology
- Cell Proliferation
- Cells, Cultured
- Disease Models, Animal
- Female
- Humans
- Hypersensitivity/immunology
- Hypersensitivity/pathology
- Immunity, Innate
- Interleukin-33/administration & dosage
- Interleukin-33/immunology
- Lung/cytology
- Lung/immunology
- Lung/pathology
- Lymphocytes/immunology
- Lymphocytes/metabolism
- Mice
- Mice, Knockout
- Nippostrongylus/immunology
- Primary Cell Culture
- Prostaglandin D2/immunology
- Prostaglandin D2/metabolism
- Receptors, Immunologic/genetics
- Receptors, Immunologic/immunology
- Receptors, Immunologic/metabolism
- Receptors, Prostaglandin/genetics
- Receptors, Prostaglandin/immunology
- Receptors, Prostaglandin/metabolism
- Recombinant Proteins/administration & dosage
- Recombinant Proteins/immunology
- Strongylida Infections/immunology
- Strongylida Infections/parasitology
- Strongylida Infections/pathology
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Affiliation(s)
- Oyebola O Oyesola
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY 14850
- Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14850; and
- Department of Immunology, University of Washington, Seattle, WA 98109
| | - Carolina Duque
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY 14850
- Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14850; and
| | - Linda C Huang
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY 14850
- Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14850; and
| | - Elisabeth M Larson
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY 14850
- Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14850; and
| | - Simon P Früh
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY 14850
- Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14850; and
| | - Lauren M Webb
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY 14850
- Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14850; and
- Department of Immunology, University of Washington, Seattle, WA 98109
| | - Seth A Peng
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY 14850
- Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14850; and
| | - Elia D Tait Wojno
- Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY 14850;
- Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14850; and
- Department of Immunology, University of Washington, Seattle, WA 98109
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Früh SP, Saikia M, Eule J, Mazulis CA, Miller JE, Cowulich JM, Oyesola OO, Webb LM, Peng SA, Cubitt RL, Danko CG, Miller WH, Tait Wojno ED. Elevated circulating Th2 but not group 2 innate lymphoid cell responses characterize canine atopic dermatitis. Vet Immunol Immunopathol 2020; 221:110015. [PMID: 32058160 DOI: 10.1016/j.vetimm.2020.110015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/17/2020] [Accepted: 01/23/2020] [Indexed: 12/11/2022]
Abstract
Atopic dermatitis (AD) is an allergic skin disease that causes significant morbidity and affects multiple species. AD is highly prevalent in companion dogs, and the clinical management of the disease remains challenging. An improved understanding of the immunologic and genetic pathways that lead to disease could inform the development of novel treatments. In allergic humans and mouse models of AD, the disease is associated with Th2 and group 2 innate lymphoid cell (ILC2) activation that drives type 2 inflammation. Type 2 inflammation also appears to be associated with AD in dogs, but gaps remain in our understanding of how key type 2-associated cell types such as canine Th2 cells and ILC2s contribute to the pathogenesis of canine AD. Here, we describe previously uncharacterized canine ILC2-like cells and Th2 cells ex vivo that produced type 2 cytokines and expressed the transcription factor Gata3. Increased circulating Th2 cells were associated with chronic canine AD. Single-cell RNA sequencing revealed a unique gene expression signature in T cells in dogs with AD. These findings underline the importance of pro-allergic Th2 cells in orchestrating AD and provide new methods and pathways that can inform the development of improved therapies.
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Affiliation(s)
- Simon P Früh
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Ithaca, NY 14853, USA
| | - Mridusmita Saikia
- Baker Institute for Animal Health and Department of Biomedical Sciences, Ithaca, NY 14853, USA
| | - Jeremy Eule
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Ithaca, NY 14853, USA
| | - Christina A Mazulis
- Section of Dermatology and Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA
| | - Julia E Miller
- Section of Dermatology and Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA
| | - Joby M Cowulich
- Section of Dermatology and Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA
| | - Oyebola O Oyesola
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Ithaca, NY 14853, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA
| | - Lauren M Webb
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Ithaca, NY 14853, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA
| | - Seth A Peng
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Ithaca, NY 14853, USA
| | - Rebecca L Cubitt
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Ithaca, NY 14853, USA
| | - Charles G Danko
- Baker Institute for Animal Health and Department of Biomedical Sciences, Ithaca, NY 14853, USA
| | - William H Miller
- Section of Dermatology and Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA
| | - Elia D Tait Wojno
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Ithaca, NY 14853, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA.
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Ramírez-Labrada AG, Isla D, Artal A, Arias M, Rezusta A, Pardo J, Gálvez EM. The Influence of Lung Microbiota on Lung Carcinogenesis, Immunity, and Immunotherapy. Trends Cancer 2020; 6:86-97. [PMID: 32061309 DOI: 10.1016/j.trecan.2019.12.007] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 12/12/2019] [Indexed: 12/20/2022]
Abstract
Microbiota have emerged as key modulators of both the carcinogenic process and the immune response against cancer cells, and, thus, it seems to influence the efficacy of immunotherapy. While most studies have focused on analyzing the influence of gut microbiota, its composition substantially differs from that in the lung. Here, we describe how microbial life in the lungs is associated with host immune status in the lungs and, thus, how the identification of the microbial populations in the lower respiratory tract rather than in the gut might be key to understanding the lung carcinogenic process and to predict the efficacy of different treatments. Understanding the influence of lung microbiota on host immunity may identify new therapeutic targets and help to design new immunotherapy approaches to treat lung cancer.
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Affiliation(s)
- Ariel G Ramírez-Labrada
- Unidad de Nanotoxicología e Inmunotoxicología (UNATI), Instituto de Investigación Sanitaria Aragón (IIS Aragón), Centro de Investigación Biomédica de Aragón (CIBA), Zaragoza, Spain
| | - Dolores Isla
- Medical Oncology Department, Instituto de Investigación Sanitaria Aragón, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain
| | - Angel Artal
- Medical Oncology Department, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Maykel Arias
- Instituto de Carboquímica ICB-CSIC, Zaragoza, Spain
| | - Antonio Rezusta
- Department of Microbiology, Hospital Universitario Miguel Servet, Zaragoza, Spain; Department of Microbiology, Preventive Medicine and Public Health, University of Zaragoza, Zaragoza, Spain
| | - Julián Pardo
- Department of Microbiology, Preventive Medicine and Public Health, University of Zaragoza, Zaragoza, Spain; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain; Aragón I + D Foundation (ARAID), Government of Aragon, Zaragoza, Spain
| | - Eva M Gálvez
- Instituto de Carboquímica ICB-CSIC, Zaragoza, Spain.
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Monticelli LA, Diamond JM, Saenz SA, Tait Wojno ED, Porteous MK, Cantu E, Artis D, Christie JD. Lung Innate Lymphoid Cell Composition Is Altered in Primary Graft Dysfunction. Am J Respir Crit Care Med 2020; 201:63-72. [PMID: 31394048 PMCID: PMC6938146 DOI: 10.1164/rccm.201906-1113oc] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 08/07/2019] [Indexed: 01/08/2023] Open
Abstract
Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation, but the immunologic mechanisms are poorly understood. Innate lymphoid cells (ILC) are a heterogeneous family of immune cells regulating pathologic inflammation and beneficial tissue repair. However, whether changes in donor-derived lung ILC populations are associated with PGD development has never been examined.Objectives: To determine whether PGD in chronic obstructive pulmonary disease or interstitial lung disease transplant recipients is associated with alterations in ILC subset composition within the allograft.Methods: We performed a single-center cohort study of lung transplantation patients with surgical biopsies of donor tissue taken before, and immediately after, allograft reperfusion. Donor immune cells from 18 patients were characterized phenotypically by flow cytometry for single-cell resolution of distinct ILC subsets. Changes in the percentage of ILC subsets with reperfusion or PGD (grade 3 within 72 h) were assessed.Measurements and Main Results: Allograft reperfusion resulted in significantly decreased frequencies of natural killer cells and a trend toward reduced ILC populations, regardless of diagnosis (interstitial lung disease or chronic obstructive pulmonary disease). Seven patients developed PGD (38.9%), and PGD development was associated with selective reduction of the ILC2 subset after reperfusion. Conversely, patients without PGD exhibited significantly higher ILC1 frequencies before reperfusion, accompanied by elevated ILC2 frequencies after allograft reperfusion.Conclusions: The composition of donor ILC subsets is altered after allograft reperfusion and is associated with PGD development, suggesting that ILCs may be involved in regulating lung injury in lung transplant recipients.
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Affiliation(s)
- Laurel A. Monticelli
- Division of Pulmonary and Critical Care Medicine and
- Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, New York; and
| | | | - Steven A. Saenz
- Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, New York; and
| | - Elia D. Tait Wojno
- Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, New York; and
| | | | - Edward Cantu
- Division of Cardiovascular Surgery, Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David Artis
- Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, New York; and
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Galeas-Pena M, McLaughlin N, Pociask D. The role of the innate immune system on pulmonary infections. Biol Chem 2019; 400:443-456. [PMID: 29604208 DOI: 10.1515/hsz-2018-0304] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/19/2018] [Indexed: 12/15/2022]
Abstract
Inhalation is required for respiration and life in all vertebrates. This process is not without risk, as it potentially exposes the host to environmental pathogens with every breath. This makes the upper respiratory tract one of the most common routes of infection and one of the leading causes of morbidity and mortality in the world. To combat this, the lung relies on the innate immune defenses. In contrast to the adaptive immune system, the innate immune system does not require sensitization, previous exposure or priming to attack foreign particles. In the lung, the innate immune response starts with the epithelial barrier and mucus production and is reinforced by phagocytic cells and T cells. These cells are vital for the production of cytokines, chemokines and anti-microbial peptides that are critical for clearance of infectious agents. In this review, we discuss all aspects of the innate immune response, with a special emphasis on ways to target aspects of the immune response to combat antibiotic resistant bacteria.
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Affiliation(s)
- Michelle Galeas-Pena
- Department of Pulmonary Critical Care and Environmental Medicine, Tulane University School of Medicine, 333 S. Liberty St., New Orleans, LA 70112, USA
| | - Nathaniel McLaughlin
- Department of Pulmonary Critical Care and Environmental Medicine, Tulane University School of Medicine, 333 S. Liberty St., New Orleans, LA 70112, USA
| | - Derek Pociask
- Department of Pulmonary Critical Care and Environmental Medicine, Tulane University School of Medicine, 333 S. Liberty St., New Orleans, LA 70112, USA
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45
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Teng F, Goc J, Zhou L, Chu C, Shah MA, Eberl G, Sonnenberg GF. A circadian clock is essential for homeostasis of group 3 innate lymphoid cells in the gut. Sci Immunol 2019; 4:eaax1215. [PMID: 31586011 PMCID: PMC7008004 DOI: 10.1126/sciimmunol.aax1215] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 08/29/2019] [Indexed: 12/12/2022]
Abstract
Group 3 innate lymphoid cells (ILC3s) critically orchestrate host-microbe interactions in the healthy mammalian intestine and become substantially impaired in the context of inflammatory bowel disease (IBD). However, the molecular pathways controlling the homeostasis of ILC3s remain incompletely defined. Here, we identify that intestinal ILC3s are highly enriched in expression of genes involved in the circadian clock and exhibit diurnal oscillations of these pathways in response to light cues. Classical ILC3 effector functions also exhibited diurnal oscillations, and lineage-specific deletion of BMAL1, a master regulator of the circadian clock, resulted in markedly reduced ILC3s selectively in the intestine. BMAL1-deficient ILC3s exhibit impaired expression of Nr1d1 and Per3, hyperactivation of RORγt-dependent target genes, and elevated proapoptotic pathways. Depletion of the microbiota with antibiotics partially reduced the hyperactivation of BMAL1-deficient ILC3s and restored cellular homeostasis in the intestine. Last, ILC3s isolated from the inflamed intestine of patients with IBD exhibit substantial alterations in expression of several circadian-related genes. Our results collectively define that circadian regulation is essential for the homeostasis of ILC3s in the presence of a complex intestinal microbiota and that this pathway is disrupted in the context of IBD.
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Affiliation(s)
- Fei Teng
- Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Jeremy Goc
- Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Lei Zhou
- Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Coco Chu
- Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Manish A Shah
- Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, NY, USA
| | - Gérard Eberl
- Institut Pasteur, Microenvironment and Immunity Unit, Paris, France
| | - Gregory F Sonnenberg
- Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
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Lewis G, Wang B, Shafiei Jahani P, Hurrell BP, Banie H, Aleman Muench GR, Maazi H, Helou DG, Howard E, Galle-Treger L, Lo R, Santosh S, Baltus A, Bongers G, San-Mateo L, Gilliland FD, Rehan VK, Soroosh P, Akbari O. Dietary Fiber-Induced Microbial Short Chain Fatty Acids Suppress ILC2-Dependent Airway Inflammation. Front Immunol 2019; 10:2051. [PMID: 31620118 PMCID: PMC6760365 DOI: 10.3389/fimmu.2019.02051] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 08/14/2019] [Indexed: 12/21/2022] Open
Abstract
Group 2 Innate lymphoid cells (ILC2) contribute significantly to allergic inflammation. However, the role of microbiota on ILC2s remains to be unraveled. Here we show that short chain fatty acids (SCFAs), such as butyrate, derived from fermentation of dietary fibers by the gut microbiota inhibit pulmonary ILC2 functions and subsequent development of airway hyperreactivity (AHR). We further show that SCFAs modulate GATA3, oxidative phosphorylation, and glycolytic metabolic pathways in pulmonary ILC2s. The observed phenotype is associated with increased IL-17a secretion by lung ILC2s and linked to enhanced neutrophil recruitment to the airways. Finally, we show that butyrate-producing gut bacteria in germ-free mice effectively suppress ILC2-driven AHR. Collectively, our results demonstrate a previously unrecognized role for microbial-derived SCFAs on pulmonary ILC2s in the context of AHR. The data suggest strategies aimed at modulating metabolomics and microbiota in the gut, not only to treat, but to prevent lung inflammation and asthma.
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Affiliation(s)
- Gavin Lewis
- Janssen Research and Development, San Diego, CA, United States
| | - Bowen Wang
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Pedram Shafiei Jahani
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Benjamin P. Hurrell
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Homayon Banie
- Janssen Research and Development, San Diego, CA, United States
| | | | - Hadi Maazi
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Doumet Georges Helou
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Emily Howard
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Lauriane Galle-Treger
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Richard Lo
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Swetha Santosh
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Andrew Baltus
- Janssen Research and Development, Spring House, PA, United States
| | - Gerrold Bongers
- Janssen Research and Development, Spring House, PA, United States
| | - Lani San-Mateo
- Janssen Research and Development, Spring House, PA, United States
| | - Frank D. Gilliland
- Division of Environmental Health, Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States
| | - Virender K. Rehan
- Division of Neonatology, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Pejman Soroosh
- Janssen Research and Development, San Diego, CA, United States
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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Abstract
Bladder cancer is an important public health concern owing to its prevalence, high recurrence risk and treatment failures. Maintaining the equilibrium between prompt and effective immunity and an excessive and protracted immune response is critical for successful immune defence. This delicate balance is ensured by intrinsic or extrinsic immunoregulatory mechanisms. Intrinsic control of immune cell activation is mediated by stimulatory and inhibitory receptors expressed on the effector cell itself, whereas extrinsic control is mediated via other immune cells by cell-cell contact and/or secretion of inhibitory factors. Tumours can exacerbate these immunosuppressive pathways, fostering a tolerant microenvironment. These mechanisms have previously been poorly described in urothelial carcinoma, but a growing body of evidence highlights the key role of immune regulation in bladder cancer. This process includes immune checkpoints (mostly programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1)), as well as regulatory T cells, myeloid-derived suppressor cells, tumour-associated macrophages and type 2 innate and adaptive lymphocytes. For each component, quantitative and qualitative alterations, clinical relevance and potential targeting strategies are currently being explored. An improved understanding of immune regulation pathways in bladder cancer development, recurrence and progression will help in the design of novel diagnostic and prognostic tools as well as treatments.
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Asthma and Food Allergy: Which Risks? ACTA ACUST UNITED AC 2019; 55:medicina55090509. [PMID: 31438462 PMCID: PMC6780261 DOI: 10.3390/medicina55090509] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 08/15/2019] [Accepted: 08/16/2019] [Indexed: 11/16/2022]
Abstract
Over the past few decades, an increase in the prevalence of asthma and food allergy has been observed in the pediatric population. In infants, food sensitization, particularly to egg, has increased the risk of developing allergic asthma. This is even more likely if sensitization to food allergens occurs early within the first few years of life. It is indeed known that both diseases may be present simultaneously in the pediatric population, but coexistence may negatively influence the severity of both conditions by increasing the risk of life-threatening asthmatic episodes as well as food-related anaphylaxis. Therefore, an accurate clinical and phenotype characterization of this high-risk group of children with both asthma and food allergy and a more aggressive management might lead to reducing related morbidity and mortality. The aim of this review is to provide an updated overview on the close link between food allergy and asthma and their negative mutual influence.
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Cavagnero KJ, Badrani JH, Naji LH, Amadeo MB, Shah VS, Gasparian S, Pham A, Wang AW, Seumois G, Croft M, Broide DH, Doherty TA. Unconventional ST2- and CD127-negative lung ILC2 populations are induced by the fungal allergen Alternaria alternata. J Allergy Clin Immunol 2019; 144:1432-1435.e9. [PMID: 31369800 DOI: 10.1016/j.jaci.2019.07.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 07/08/2019] [Accepted: 07/25/2019] [Indexed: 12/19/2022]
Affiliation(s)
| | - Jana H Badrani
- Department of Medicine, University of California, San Diego, Calif
| | - Luay H Naji
- Department of Medicine, University of California, San Diego, Calif
| | - Michael B Amadeo
- Department of Medicine, University of California, San Diego, Calif
| | - Veranca S Shah
- Department of Medicine, University of California, San Diego, Calif
| | | | - Alexa Pham
- Department of Medicine, University of California, San Diego, Calif
| | - Alice W Wang
- La Jolla Institute for Allergy and Immunology, La Jolla, Calif
| | - Grégory Seumois
- La Jolla Institute for Allergy and Immunology, La Jolla, Calif
| | - Michael Croft
- Department of Medicine, University of California, San Diego, Calif; La Jolla Institute for Allergy and Immunology, La Jolla, Calif
| | - David H Broide
- Department of Medicine, University of California, San Diego, Calif
| | - Taylor A Doherty
- Department of Medicine, University of California, San Diego, Calif.
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50
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Pokrovskii M, Hall JA, Ochayon DE, Yi R, Chaimowitz NS, Seelamneni H, Carriero N, Watters A, Waggoner SN, Littman DR, Bonneau R, Miraldi ER. Characterization of Transcriptional Regulatory Networks that Promote and Restrict Identities and Functions of Intestinal Innate Lymphoid Cells. Immunity 2019; 51:185-197.e6. [PMID: 31278058 PMCID: PMC6863506 DOI: 10.1016/j.immuni.2019.06.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 03/12/2019] [Accepted: 06/04/2019] [Indexed: 12/14/2022]
Abstract
Innate lymphoid cells (ILCs) promote tissue homeostasis and immune defense but also contribute to inflammatory diseases. ILCs exhibit phenotypic and functional plasticity in response to environmental stimuli, yet the transcriptional regulatory networks (TRNs) that control ILC function are largely unknown. Here, we integrate gene expression and chromatin accessibility data to infer regulatory interactions between transcription factors (TFs) and genes within intestinal type 1, 2, and 3 ILC subsets. We predicted the "core" TFs driving ILC identities, organized TFs into cooperative modules controlling distinct gene programs, and validated roles for c-MAF and BCL6 as regulators affecting type 1 and type 3 ILC lineages. The ILC network revealed alternative-lineage-gene repression, a mechanism that may contribute to reported plasticity between ILC subsets. By connecting TFs to genes, the TRNs suggest means to selectively regulate ILC effector functions, while our network approach is broadly applicable to identifying regulators in other in vivo cell populations.
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Affiliation(s)
- Maria Pokrovskii
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - Jason A Hall
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
| | - David E Ochayon
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Ren Yi
- Departments of Biology and Computer Science, New York University, NY 10003, USA
| | - Natalia S Chaimowitz
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Harsha Seelamneni
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Nicholas Carriero
- Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA
| | - Aaron Watters
- Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA
| | - Stephen N Waggoner
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Dan R Littman
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute.
| | - Richard Bonneau
- Departments of Biology and Computer Science, New York University, NY 10003, USA; Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA.
| | - Emily R Miraldi
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Divisions of Immunobiology and Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
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