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Yoshimura K, Zou G, Fan Y, Yamashita K, Wang L, Wu J, Wang R, Shao S, Scott AW, Jin J, Pizzi MP, Yao X, Brown CA, Wang L, Gan Q, Waters RE, Yin F, Song S, Dhar SS, Ajani JA. HSP90 inhibitor AUY922 suppresses tumor growth and modulates immune response through YAP1-TEAD pathway inhibition in gastric cancer. Cancer Lett 2025; 610:217354. [PMID: 39603381 DOI: 10.1016/j.canlet.2024.217354] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 11/18/2024] [Accepted: 11/24/2024] [Indexed: 11/29/2024]
Abstract
Heat shock protein 90 (HSP90), a vital chaperone involved in the folding and stabilization of various cellular proteins, regulates key functions in many tumor cells. In the context of gastric adenocarcinoma (GAC), where HSP90's role remains largely unexplored, we aimed to investigate the significance of HSP90 inhibitor, AUY922, in regulating the YAP1/TEAD pathway and its association with the tumor immune microenvironment (TME). Our results showed that AUY922 effectively inhibited GAC aggressiveness in both the invitro and invivo models, induced apoptosis, and cell-cycle arrest. Various functional assays elucidated that AUY922 potently inhibited the expression and interaction among YAP1/TEAD and HSP90, resulting in down-regulation of target functional genes. AUY922 additionally altered the tumor microenvironment (TME) into an inflamed state with increased cytokine production in T cells, including interferon gamma, granzyme B, and perforin, and inhibited M2 polarization of tumor-associated macrophages, rendering it a favorable partner for immune checkpoint inhibition. Our findings highlighted the suggestion of targeting HSP90 in GAC therapy via down-regulating YAP1/TEAD signaling. Additionally, our results suggest that AUY922's ability to reshape the GAC TME favoring the host sets the stage for a clinical trial that combines HSP90 and checkpoint inhibition, where HSP90 could serve as a biomarker for patient selection.
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Affiliation(s)
- Katsuhiro Yoshimura
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Gengyi Zou
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yibo Fan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kohei Yamashita
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lingzhi Wang
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jingjing Wu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ruiping Wang
- Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shan Shao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ailing W Scott
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jiankang Jin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Melissa Pool Pizzi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaodan Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Calena-Abel Brown
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Linghua Wang
- Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qiong Gan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rebecca E Waters
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Feng Yin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shumei Song
- Coriell Institute for Medical Research, NJ, USA
| | - Shilpa S Dhar
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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He Y, Han Z, Zhang Q, Liu L, Chang J. Role of fibroblasts in nonfibrotic autoimmune skin diseases. Mol Med 2024; 30:178. [PMID: 39420283 PMCID: PMC11488258 DOI: 10.1186/s10020-024-00949-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 10/03/2024] [Indexed: 10/19/2024] Open
Abstract
Autoimmune diseases, a disease characterized by immune imbalance caused by the human immune system mistakenly attacking its own components, include vitiligo, psoriasis and atopic dermatitis (AD). Previous studies on autoimmune diseases have focused mainly on immune cells, keratinocytes and endothelial cells. Fibroblasts, the main cells that secrete the extracellular matrix (ECM) in the dermis, have been studied thoroughly in terms of fibrosis and wound healing. However, an increasing number of studies have shown that fibroblasts play an important role in nonfibrotic autoimmune skin diseases. In this article, the previously reported role of fibroblasts in nonfibrous autoimmune skin diseases such as psoriasis, vitiligo and AD is summarized to provide new ideas for the treatment of this disease.
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Affiliation(s)
- Yuexi He
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, China
- Department of Dermatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Zhenxin Han
- Department of Dermatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
- Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Qiuli Zhang
- Department of Dermatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Lin Liu
- Department of Dermatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Jianmin Chang
- Department of Dermatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
- Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China.
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Sommer C, Neuhaus V, Gogesch P, Flandre T, Dehmel S, Sewald K. Type 2 responses determine skin rash during recombinant interleukin-2 therapy. J Immunotoxicol 2024; 21:S48-S59. [PMID: 39655497 DOI: 10.1080/1547691x.2024.2343359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 03/11/2024] [Accepted: 04/10/2024] [Indexed: 12/18/2024] Open
Abstract
The skin is the organ most often affected by adverse drug reactions. Although these cutaneous adverse drug reactions (CADRs) often are mild, they represent a major burden for patients. One of the drugs inducing CADRs is aldesleukin, a recombinant interleukin-2 (recIL-2) originally approved to treat malignant melanoma and metastatic renal cell carcinoma which frequently led to skin rashes when applied in high doses for anti-cancer therapy. Skin rashes and other side effects, together with poor efficacy led to a drawback of the therapeutic, but modified recIL-2 molecules are on the rise to treat both cancer and inflammatory diseases such as autoimmunity. Still, pathophysiological mechanisms of recIL-2-induced skin rashes are not understood. In the study reported here, a hypothetical literature-based immune-related adverse outcome pathway (irAOP) was developed to identify possible key cells and molecules in recIL-2-induced skin rash. Using this approach, a hypothesis was formed that the induced immune response predominantly is Type 2-driven by T-helper and innate lymphoid cells, leading to the occurrence of cutaneous side effects during recIL-2 therapy. This paper further discusses mechanisms beyond the proposed irAOP which might add to the pathology but currently are less-studied. Together, this hypothetic irAOP forms a basis to clarify possible cellular and molecular interactions leading to recIL-2-induced skin rash. This might be used to adapt existing or develop new test systems to help predict and prevent cutaneous side effects in future IL-2-based or similar therapies.
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Affiliation(s)
- Charline Sommer
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Department for Preclinical Pharmacology and Toxicology, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hanover, Germany
| | - Vanessa Neuhaus
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Department for Preclinical Pharmacology and Toxicology, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hanover, Germany
| | | | | | - Susann Dehmel
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Department for Preclinical Pharmacology and Toxicology, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hanover, Germany
| | - Katherina Sewald
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Department for Preclinical Pharmacology and Toxicology, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hanover, Germany
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4
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Ansari AW, Ahmad F, Alam MA, Raheed T, Zaqout A, Al-Maslamani M, Ahmad A, Buddenkotte J, Al-Khal A, Steinhoff M. Virus-Induced Host Chemokine CCL2 in COVID-19 Pathogenesis: Potential Prognostic Marker and Target of Anti-Inflammatory Strategy. Rev Med Virol 2024; 34:e2578. [PMID: 39192485 DOI: 10.1002/rmv.2578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 07/28/2024] [Accepted: 08/14/2024] [Indexed: 08/29/2024]
Abstract
A wide variety of inflammatory mediators, mainly cytokines and chemokines, are induced during SARS CoV-2 infection. Among these proinflammatory mediators, chemokines tend to play a pivotal role in virus-mediated immunopathology. The C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1) is a potent proinflammatory cytokine and strong chemoattractant of monocytes, macrophages and CD4+ T cells bearing C-C chemokine receptor type-2 (CCR2). Besides controlling immune cell trafficking, CCL2 is also involved in multiple pathophysiological processes including systemic hyperinflammation associated cytokine release syndrome (CRS), organ fibrosis and blood coagulation. These pathological features are commonly manifested in severe and fatal cases of COVID-19. Given the crucial role of CCL2 in COVID-19 pathogenesis, the CCL2:CCR2 axis may constitute a potential therapeutic target to control virus-induced hyperinflammation and multi-organ dysfunction. Herein we describe recent advances on elucidating the role of CCL2 in COVID-19 pathogenesis, prognosis, and a potential target of anti-inflammatory interventions.
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Affiliation(s)
- Abdul Wahid Ansari
- Dermatology Institute, Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Fareed Ahmad
- Dermatology Institute, Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Majid Ali Alam
- Dermatology Institute, Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Thesni Raheed
- Dermatology Institute, Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ahmed Zaqout
- Division of Infectious Diseases, Department of Medicine, Hamad Medical Corporation, Doha, Qatar
- Communicable Diseases Centre, Hamad Medical Corporation, Doha, Qatar
| | - Muna Al-Maslamani
- Division of Infectious Diseases, Department of Medicine, Hamad Medical Corporation, Doha, Qatar
- Communicable Diseases Centre, Hamad Medical Corporation, Doha, Qatar
| | - Aamir Ahmad
- Dermatology Institute, Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Joerg Buddenkotte
- Dermatology Institute, Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar
| | - Abdullatif Al-Khal
- Division of Infectious Diseases, Department of Medicine, Hamad Medical Corporation, Doha, Qatar
- Communicable Diseases Centre, Hamad Medical Corporation, Doha, Qatar
| | - Martin Steinhoff
- Dermatology Institute, Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar
- Weill Cornell Medicine-Qatar, Doha, Qatar
- Dermatology, Weill Cornell University, New York, New York, USA
- College of Medicine, Qatar University, Doha, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
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Petruccioli E, Sbarra S, Vita S, Salmi A, Cuzzi G, De Marco P, Matusali G, Navarra A, Pierelli L, Grifoni A, Sette A, Maggi F, Nicastri E, Goletti D. Characterization of the Monkeypox Virus [MPX]-Specific Immune Response in MPX-Cured Individuals Using Whole Blood to Monitor Memory Response. Vaccines (Basel) 2024; 12:964. [PMID: 39339995 PMCID: PMC11436000 DOI: 10.3390/vaccines12090964] [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: 07/17/2024] [Revised: 08/13/2024] [Accepted: 08/23/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Monkeypox (Mpox) is a zoonotic disease caused by monkeypox virus (MPXV), an Orthopoxvirus (OPXV). Since we are observing the first MPXV outbreak outside the African continent, the general population probably does not have a pre-existing memory response for MPXV but may have immunity against the previous smallpox vaccine based on a live replicating Vaccinia strain (VACV). Using a whole blood platform, we aim to study the MPXV- T-cell-specific response in Mpox-cured subjects. METHODS We enrolled 16 subjects diagnosed with Mpox in the previous 3-7 months and 15 healthy donors (HD) with no recent vaccination history. Whole blood was stimulated overnight with MPXV and VACV peptides to elicit CD4 and CD8 T-cell-specific responses, which were evaluated by ELISA and multiplex assay. RESULTS Mpox-cured subjects showed a significant IFN-γ T-cell response to MPXV and VACV. Besides IFN-γ, IL-6, IP-10, IL-8, IL-2, G-CSF, MCP-1, MIP1-α, MIP-1β, IL-1Rα, and IL-5 were significantly induced after specific stimulation compared to the unstimulated control. The specific response was mainly induced by the CD4 peptides MPX-CD4-E and VACV-CD4. CONCLUSIONS We showed that MPXV-specific responses have a mixed Th1- and Th2-response in a whole blood platform assay, which may be useful for monitoring the specific immunity induced by vaccination or infection.
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Affiliation(s)
- Elisa Petruccioli
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (E.P.); (S.S.)
| | - Settimia Sbarra
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (E.P.); (S.S.)
| | - Serena Vita
- Highly Infectious Diseases Isolation Unit, Clinical Department, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy
| | - Andrea Salmi
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (E.P.); (S.S.)
| | - Gilda Cuzzi
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (E.P.); (S.S.)
| | - Patrizia De Marco
- Highly Infectious Diseases Isolation Unit, Clinical Department, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy
| | - Giulia Matusali
- Laboratory of Virology and Biosafety Laboratories, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy
| | - Assunta Navarra
- Clinical Epidemiology Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy
| | - Luca Pierelli
- Unità Operativa Complessa (UOC) Transfusion Medicine and Stem Cell, San Camillo Forlanini Hospital, 00149 Rome, Italy
| | - Alba Grifoni
- Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Alessandro Sette
- Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA
| | - Fabrizio Maggi
- Laboratory of Virology and Biosafety Laboratories, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy
| | - Emanuele Nicastri
- Highly Infectious Diseases Isolation Unit, Clinical Department, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy
| | - Delia Goletti
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (E.P.); (S.S.)
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Masson JD, Badran G, Gherardi RK, Authier FJ, Crépeaux G. Widespread Myalgia and Chronic Fatigue: Phagocytes from Macrophagic Myofasciitis Patients Exposed to Aluminum Oxyhydroxide-Adjuvanted Vaccine Exhibit Specific Inflammatory, Autophagic, and Mitochondrial Responses. TOXICS 2024; 12:491. [PMID: 39058143 PMCID: PMC11281175 DOI: 10.3390/toxics12070491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 06/29/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024]
Abstract
(1) Background: Macrophagic myofasciitis (MMF) is an inflammatory histopathological lesion demonstrating long-term biopersistence of vaccine-derived aluminum adjuvants within muscular phagocytic cells. Affected patients suffer from widespread myalgia and severe fatigue consistent with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a poorly understood disorder suspected to result from chronic immune stimulation by infectious and inorganic particles. (2) Methods: In this study we determined the immuno-metabolic properties of MMF phagocytic cells compared to controls, at rest and upon exposure to aluminum oxyhydroxide adjuvant, with or without adsorbed antigens, using protein quantification and an oxygen consumption assay. (3) Results: MMF and control cells similarly internalized the adjuvant and vaccine but MMF cells specifically expressed Rubicon and Nox2, two molecules unique to the LC3-associated phagocytosis (LAP) machinery, a non-canonical autophagic pathway able to downregulate canonical autophagy. MMF cells exhibited an altered inflammatory secretome, producing more pain-inducing CXC chemokines and less TNF-α than controls, consistent with chronic myalgia and exhaustion of the immune system previously documented in ME/CFS. MMF cells exhibited mitochondrial metabolism dysfunction, with exacerbated reaction to adjuvanted vaccine, contrasting with limited spare respiratory capacity and marked proton leak weakening energy production. (4) Conclusions: MMF phagocytes seemingly use LAP to handle aluminum oxyhydroxide vaccine particles, secrete pain-inducing molecules, and exhibit exacerbated metabolic reaction to the vaccine with limited capacity to respond to ongoing energetic requests.
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Affiliation(s)
- Jean-Daniel Masson
- Institut National de la Santé Et de la Recherche Médicale, Institut Mondor de Recherche Biomédicale, Université Paris Est Créteil, F-94010 Creteil, France
| | - Ghidaa Badran
- Institut National de la Santé Et de la Recherche Médicale, Institut Mondor de Recherche Biomédicale, Université Paris Est Créteil, F-94010 Creteil, France
| | - Romain K. Gherardi
- Institut National de la Santé Et de la Recherche Médicale, Institut Mondor de Recherche Biomédicale, Université Paris Est Créteil, F-94010 Creteil, France
- Hôpitaux Universitaires Henri Mondor, Service d’Histologie/Centre Expert de Pathologie Neuromusculaire, Assistance Publique-Hôpitaux de Paris, F-94010 Creteil, France
| | - François-Jérôme Authier
- Institut National de la Santé Et de la Recherche Médicale, Institut Mondor de Recherche Biomédicale, Université Paris Est Créteil, F-94010 Creteil, France
- Hôpitaux Universitaires Henri Mondor, Service d’Histologie/Centre Expert de Pathologie Neuromusculaire, Assistance Publique-Hôpitaux de Paris, F-94010 Creteil, France
| | - Guillemette Crépeaux
- Institut National de la Santé Et de la Recherche Médicale, Institut Mondor de Recherche Biomédicale, Université Paris Est Créteil, F-94010 Creteil, France
- Ecole Nationale Vétérinaire d’Alfort, Institut Mondor de Recherche Biomédicale, F-94700 Maisons Alfort, France
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Gao Y, Chen S, Jiao S, Fan Y, Li X, Tan N, Fang J, Xu L, Huang Y, Zhao J, Guo S, Liu T, Xu W. ATG5-regulated CCL2/MCP-1 production in myeloid cells selectively modulates anti-malarial CD4 + Th1 responses. Autophagy 2024; 20:1398-1417. [PMID: 38368631 PMCID: PMC11210915 DOI: 10.1080/15548627.2024.2319512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/06/2024] [Accepted: 02/12/2024] [Indexed: 02/20/2024] Open
Abstract
Parasite-specific CD4+ Th1 cell responses are the predominant immune effector for controlling malaria infection; however, the underlying regulatory mechanisms remain largely unknown. This study demonstrated that ATG5 deficiency in myeloid cells can significantly inhibit the growth of rodent blood-stage malarial parasites by selectively enhancing parasite-specific CD4+ Th1 cell responses. This effect was independent of ATG5-mediated canonical and non-canonical autophagy. Mechanistically, ATG5 deficiency suppressed FAS-mediated apoptosis of LY6G- ITGAM/CD11b+ ADGRE1/F4/80- cells and subsequently increased CCL2/MCP-1 production in parasite-infected mice. LY6G- ITGAM+ ADGRE1- cell-derived CCL2 selectively interacted with CCR2 on CD4+ Th1 cells for their optimized responses through the JAK2-STAT4 pathway. The administration of recombinant CCL2 significantly promoted parasite-specific CD4+ Th1 responses and suppressed malaria infection. Conclusively, our study highlights the previously unrecognized role of ATG5 in modulating myeloid cells apoptosis and sequentially affecting CCL2 production, which selectively promotes CD4+ Th1 cell responses. Our findings provide new insights into the development of immune interventions and effective anti-malarial vaccines.Abbreviations: ATG5: autophagy related 5; CBA: cytometric bead array; CCL2/MCP-1: C-C motif chemokine ligand 2; IgG: immunoglobulin G; IL6: interleukin 6; IL10: interleukin 10; IL12: interleukin 12; MFI: mean fluorescence intensity; JAK2: Janus kinase 2; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; pRBCs: parasitized red blood cells; RUBCN: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; STAT4: signal transducer and activator of transcription 4; Th1: T helper 1 cell; Tfh: follicular helper cell; ULK1: unc-51 like kinase 1.
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Affiliation(s)
- Yuanli Gao
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Suilin Chen
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
- Clinical Laboratory Diagnostic Center, General Hospital of Xinjiang Military Region, Urumqi, China
| | - Shiming Jiao
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yongling Fan
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiuxiu Li
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
- The School of Medicine, Chongqing University, Chongqing, China
| | - Nie Tan
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jiaqin Fang
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Luming Xu
- Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yi Huang
- Biomedical Analysis Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jing Zhao
- Biomedical Analysis Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Shuai Guo
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Taiping Liu
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
- Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China
| | - Wenyue Xu
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
- The School of Medicine, Chongqing University, Chongqing, China
- Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China
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8
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Migayron L, Bordes S, Closs B, Seneschal J, Boniface K. Type-2 immunity associated with type-1 related skin inflammatory diseases: friend or foe? Front Immunol 2024; 15:1405215. [PMID: 38868763 PMCID: PMC11167106 DOI: 10.3389/fimmu.2024.1405215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 05/14/2024] [Indexed: 06/14/2024] Open
Abstract
Chronic inflammatory skin diseases are multifactorial diseases that combine genetic predisposition, environmental triggers, and metabolic disturbances associated with abnormal immune responses. From an immunological perspective, the better understanding of their physiopathology has demonstrated a large complex network of immune cell subsets and related cytokines that interact with both epidermal and dermal cells. For example, in type-1-associated diseases such as alopecia areata, vitiligo, and localized scleroderma, recent evidence suggests the presence of a type-2 inflammation that is well known in atopic dermatitis. Whether this type-2 immune response has a protective or detrimental impact on the development and chronicity of these diseases remains to be fully elucidated, highlighting the need to better understand its involvement for the management of patients. This mini-review explores recent insights regarding the potential role of type-2-related immunity in alopecia areata, vitiligo, and localized scleroderma.
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Affiliation(s)
- Laure Migayron
- Univ. Bordeaux, CNRS, Immuno ConcEpT, UMR 5164, Bordeaux, France
- R&D Department, SILAB, Brive-la-Gaillarde, France
| | | | | | - Julien Seneschal
- Univ. Bordeaux, CNRS, Immuno ConcEpT, UMR 5164, Bordeaux, France
- CHU de Bordeaux, Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hôpital Saint-André, UMR 5164, Bordeaux, France
| | - Katia Boniface
- Univ. Bordeaux, CNRS, Immuno ConcEpT, UMR 5164, Bordeaux, France
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9
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Calmon MS, Lemos FFB, Silva Luz M, Rocha Pinheiro SL, de Oliveira Silva LG, Correa Santos GL, Rocha GR, Freire de Melo F. Immune pathway through endometriosis to ovarian cancer. World J Clin Oncol 2024; 15:496-522. [PMID: 38689629 PMCID: PMC11056862 DOI: 10.5306/wjco.v15.i4.496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/29/2024] [Accepted: 03/18/2024] [Indexed: 04/22/2024] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.
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Affiliation(s)
- Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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10
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Mizuno M, Minato KI. Anti-inflammatory and immunomodulatory properties of polysaccharides in mushrooms. Curr Opin Biotechnol 2024; 86:103076. [PMID: 38364705 DOI: 10.1016/j.copbio.2024.103076] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 02/18/2024]
Abstract
Mushrooms are distinguished as important food-containing polysaccharides possessing potent anti-inflammatory and immunomodulating properties. These compounds belong mostly to polysaccharides that are mostly β-D-glucans. Among them, β-1,3-glucan with β-1,6 side chains of glucose residues, has more important roles in their properties. In this review, we have introduced polysaccharides mainly from Lentinula edodes and Pleurotus citrinopileatus with anti-inflammatory and immunomodulating properties. In addition, the mechanisms of activation of their physiological properties and signal cascade are also reviewed.
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Affiliation(s)
- Masashi Mizuno
- Department of Health and Nutrition, Faculty of Human Science, Osaka Aoyama University, 2-11-1 Niina, Minoh, Osaka 562-8580, Japan.
| | - Ken-Ichiro Minato
- Department of Applied Biological Chemistry, The Graduate School of Agriculture, Meijo University, Nagoya 468-8502, Japan
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11
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Dos Reis SA, Gonçalves JD, Lima KDA, Demaria TM, Costa-Bartuli E, Gomes TA, Corrêa MBC, Atella GC, Sola-Penna M, Rosa PS, Pessolani MCV, Nagajyothi J, Lara FA. Mycobacterium leprae is able to infect adipocytes, inducing lipolysis and modulating the immune response. Microbes Infect 2024; 26:105283. [PMID: 38141852 DOI: 10.1016/j.micinf.2023.105283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 12/05/2023] [Accepted: 12/19/2023] [Indexed: 12/25/2023]
Abstract
Leprosy is a chronic infectious disease caused by the intracellular bacillus Mycobacterium leprae (M. leprae), which is known to infect skin macrophages and Schwann cells. Although adipose tissue is a recognized site of Mycobacterium tuberculosis infection, its role in the histopathology of leprosy was, until now, unknown. We analyzed the M. leprae capacity to infect and persist inside adipocytes, characterizing the induction of a lipolytic phenotype in adipocytes, as well as the effect of these infected cells on macrophage recruitment. We evaluated 3T3-L1-derived adipocytes, inguinal adipose tissue of SWR/J mice, and subcutaneous adipose tissue biopsies of leprosy patients. M. leprae was able to infect 3T3-L1-derived adipocytes in vitro, presenting a strong lipolytic profile after infection, followed by significant cholesterol efflux. This lipolytic phenotype was replicated in vivo by M. leprae injection into mice inguinal adipose tissue. Furthermore, M. leprae was detected inside crown-like structures in the subcutaneous adipose tissue of multibacillary patients. These data indicate that subcutaneous adipose tissue could be an important site of infection, and probably persistence, for M. leprae, being involved in the modulation of the innate immune control in leprosy via the release of cholesterol, MCP-1, and adiponectin.
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Affiliation(s)
- Sabrina Alves Dos Reis
- Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Laboratório de Imunoterapia Celular e Gênica, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil
| | - Jessica Dias Gonçalves
- Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Karoline Dos Anjos Lima
- Laboratório de Bioquímica de Lipídeos e Lipoproteínas, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Thaina Magalhaes Demaria
- The MetaboliZSm GrouP, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Emylle Costa-Bartuli
- The MetaboliZSm GrouP, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tiago Araujo Gomes
- Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | - Georgia Correa Atella
- Laboratório de Bioquímica de Lipídeos e Lipoproteínas, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mauro Sola-Penna
- The MetaboliZSm GrouP, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | - Jyothi Nagajyothi
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ-07110, USA
| | - Flavio Alves Lara
- Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
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12
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Chiang S, Yu SE, Athni TS, Bergmark RW, Maxfield AZ, Roditi RE, Buchheit KM, Lundberg M, Mitchell MB, Lee SE. Not just snot: Local inflammatory profiles in patients with aspirin-exacerbated respiratory disease differ from patients with aspirin-tolerant chronic rhinosinusitis. Int Forum Allergy Rhinol 2024; 14:110-113. [PMID: 37325975 PMCID: PMC11660759 DOI: 10.1002/alr.23216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 06/02/2023] [Accepted: 06/12/2023] [Indexed: 06/17/2023]
Abstract
KEY POINTS IL-5, CCL2, and CXCL8 in sinus mucous are higher in patients with AERD relative to aspirin-tolerant patients with CRS These mediators are pleiotropic, leading to widescale inflammatory processes contributing to AERD AERD is not only a T2 disease but heterogeneous: this may explain the refractory nature of AERD.
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Affiliation(s)
- Simon Chiang
- Division of Otolaryngology – Head & Neck Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Sophie E. Yu
- Division of Otolaryngology – Head & Neck Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Tejas S. Athni
- Division of Otolaryngology – Head & Neck Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Regan W. Bergmark
- Division of Otolaryngology – Head & Neck Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Center for Surgery and Public Health, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Alice Z. Maxfield
- Division of Otolaryngology – Head & Neck Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Rachel E. Roditi
- Division of Otolaryngology – Head & Neck Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Kathleen M. Buchheit
- Department of Medicine, Harvard Medical School, the Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, and the Jeff and Penny Vinik Center, Boston, MA, USA
| | - Marie Lundberg
- Department of Otolaryngology - Head & Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Margaret B. Mitchell
- Division of Otolaryngology – Head & Neck Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Stella E. Lee
- Division of Otolaryngology – Head & Neck Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Center for Surgery and Public Health, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
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13
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Chen HJ, Galley JD, Verosky BG, Yang FT, Rajasekera TA, Bailey MT, Gur TL. Fetal CCL2 signaling mediates offspring social behavior and recapitulates effects of prenatal stress. Brain Behav Immun 2024; 115:308-318. [PMID: 37914098 PMCID: PMC10872760 DOI: 10.1016/j.bbi.2023.10.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 10/26/2023] [Accepted: 10/29/2023] [Indexed: 11/03/2023] Open
Abstract
Maternal stress during pregnancy is prevalent and associated with increased risk of neurodevelopmental disorders in the offspring. Maternal and offspring immune dysfunction has been implicated as a potential mechanism by which prenatal stress shapes offspring neurodevelopment; however, the impact of prenatal stress on the developing immune system has yet to be elucidated. Furthermore, there is evidence that the chemokine C-C motif chemokine ligand 2 (CCL2) plays a key role in mediating the behavioral sequelae of prenatal stress. Here, we use an established model of prenatal restraint stress in mice to investigate alterations in the fetal immune system, with a focus on CCL2. In the placenta, stress led to a reduction in CCL2 and Ccr2 expression with a concomitant decrease in leukocyte number. However, the fetal liver exhibited an inflammatory phenotype, with upregulation of Ccl2, Il6, and Lbp expression, along with an increase in pro-inflammatory Ly6CHi monocytes. Prenatal stress also disrupted chemokine signaling and increased the number of monocytes and microglia in the fetal brain. Furthermore, stress increased Il1b expression by fetal brain CD11b+ microglia and monocytes. Finally, intra-amniotic injections of recombinant mouse CCL2 partially recapitulated the social behavioral deficits in the adult offspring previously observed in the prenatal restraint stress model. Altogether, these data suggest that prenatal stress led to fetal inflammation, and that fetal CCL2 plays a role in shaping offspring social behavior.
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Affiliation(s)
- Helen J Chen
- Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Department of Psychiatry & Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Medical Scientist Training Program, The Ohio State University, Columbus, OH, United States
| | - Jeffrey D Galley
- Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Department of Psychiatry & Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Branden G Verosky
- Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Department of Psychiatry & Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Medical Scientist Training Program, The Ohio State University, Columbus, OH, United States
| | - Felix T Yang
- Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Department of Psychiatry & Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Medical Scientist Training Program, The Ohio State University, Columbus, OH, United States
| | - Therese A Rajasekera
- Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Department of Psychiatry & Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Michael T Bailey
- Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Center for Microbial Pathogenesis, The Research Institute, Nationwide Children's Hospital, Columbus, OH, United States; Biosciences Division, College of Dentistry, The Ohio State University, Columbus, OH, United States; Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Tamar L Gur
- Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Department of Psychiatry & Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, United States; Medical Scientist Training Program, The Ohio State University, Columbus, OH, United States; Department of Obstetrics & Gynecology, The Ohio State University Wexner Medical Center, Columbus OH, United States.
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14
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Deng L, Ren J, Li B, Wang Y, Jiang N, Wang Y, Cui H. Predictive value of CCL2 in the prognosis and immunotherapy response of glioblastoma multiforme. BMC Genomics 2023; 24:746. [PMID: 38057698 DOI: 10.1186/s12864-023-09674-x] [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: 03/03/2023] [Accepted: 09/12/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor with a poor prognosis. The C-C motif chemokine ligand 2 (CCL2) has shown abnormal expression associated with progression of multiple malignancies, however, its role in predicting the prognosis and immunotherapy response of GBM remains poorly understood. RESULTS CCL2 was highly expressed in GBM as analyzed by integrating CGGA, GEPIA and UALCAN online platforms, and further verified by histologic examinations, qRT-PCR analysis, and independent GEO datasets. CCL2 could serve as an independent prognostic factor for both the poor overall survival and progression-free survival of GBM patients based on TCGA data, univariate and multivariate cox analyses. Functional enrichment analysis revealed that CCL2 mainly participated in the regulation of chemokine signaling pathway and inflammatory response. Further, CCL2 expression was positively correlated with CD4 T cells, macrophages, neutrophils and myeloid dendritic cells infiltrating GBM as calculated by the TIMER2.0 algorithm. Importantly, the tumor immune dysfunction and exclusion (TIDE) algorithm showed that in CCL2-high GBM group, the expression of CD274, CTLA4, HAVCR2 and other immune checkpoints were significantly increased, and the immune checkpoint blockade (ICB) therapy was accordingly more responsive. CONCLUSIONS CCL2 can be used as a predictor of prognosis as well as immunotherapy response in GBM, offering potential clinical implications.
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Affiliation(s)
- Longfei Deng
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400715, China
| | - Jie Ren
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400715, China
| | - Benqin Li
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400715, China
| | - Yinggang Wang
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400715, China
| | - Nianfen Jiang
- Health Management Center, Southwest University Hospital, Chongqing, 400715, China
| | - Yi Wang
- Department of Endocrinology, The Ninth People's Hospital of Chongqing, Chongqing, 400799, China.
| | - Hongjuan Cui
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400715, China.
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China.
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15
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Bai M, Sun R, Cao B, Feng J, Wang J. Monocyte-related cytokines/chemokines in cerebral ischemic stroke. CNS Neurosci Ther 2023; 29:3693-3712. [PMID: 37452512 PMCID: PMC10651979 DOI: 10.1111/cns.14368] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/01/2023] [Accepted: 07/04/2023] [Indexed: 07/18/2023] Open
Abstract
AIMS Ischemic stroke is one of the leading causes of death worldwide and the most common cause of disability in Western countries. Multiple mechanisms contribute to the development and progression of ischemic stroke, and inflammation is one of the most important mechanisms. DISCUSSION Ischemia induces the release of adenosine triphosphate/reactive oxygen species, which activates immune cells to produce many proinflammatory cytokines that activate downstream inflammatory cascades to induce fatal immune responses. Research has confirmed that peripheral blood immune cells play a vital role in the immunological cascade after ischemic stroke. The role of monocytes has received much attention among numerous peripheral blood immune cells. Monocytes induce their effects by secreting cytokines or chemokines, including CCL2/CCR2, CCR4, CCR5, CD36, CX3CL1/CX3CR1, CXCL12(SDF-1), LFA-1/ICAM-1, Ly6C, MMP-2/9, NR4A1, P2X4R, P-selectin, CD40L, TLR2/4, and VCAM-1/VLA-4. Those factors play important roles in the process of monocyte recruitment, migration, and differentiation. CONCLUSION This review focuses on the function and mechanism of the cytokines secreted by monocytes in the process of ischemic stroke and provides novel targets for treating cerebral ischemic stroke.
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Affiliation(s)
- Meiling Bai
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ruize Sun
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Bin Cao
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Juan Feng
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jue Wang
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
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16
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Xu Z, Huang Y, Meese T, Van Nevel S, Holtappels G, Vanhee S, Bröker BM, Li Z, de Meester E, De Ruyck N, Van Zele T, Gevaert P, Van Nieuwerburgh F, Zhang L, Shamji MH, Wen W, Zhang N, Bachert C. The multi-omics single-cell landscape of sinus mucosa in uncontrolled severe chronic rhinosinusitis with nasal polyps. Clin Immunol 2023; 256:109791. [PMID: 37769787 DOI: 10.1016/j.clim.2023.109791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/03/2023]
Abstract
Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with elevated levels of type 2 inflammatory cytokines and raised immunoglobulin concentrations in nasal polyp tissue. By using single-cell RNA sequencing, transcriptomics, surface proteomics, and T cell and B cell receptor sequencing, we found the predominant cell types in nasal polyps were shifted from epithelial and mesenchymal cells to inflammatory cells compared to nasal mucosa from healthy controls. Broad expansions of CD4 T effector memory cells, CD4 tissue-resident memory T cells, CD8 T effector memory cells and all subtypes of B cells in nasal polyp tissues. The T and B cell receptor repertoires were skewed in NP. This study highlights the deviated immune response and remodeling mechanisms that contribute to the pathogenesis of uncontrolled severe CRSwNP. CLINICAL IMPLICATIONS: We identified differences in the cellular compositions, transcriptomes, proteomes, and deviations in the immune profiles of T cell and B cell receptors as well as alterations in the intercellular communications in uncontrolled severe CRSwNP patients versus healthy controls, which might help to define potential therapeutic targets in the future.
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Affiliation(s)
- Zhaofeng Xu
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China; Upper Airway Research Laboratory, Ghent University, Ghent, Belgium
| | - Yanran Huang
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China; Upper Airway Research Laboratory, Ghent University, Ghent, Belgium; Department of Allergy, Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, PR China; Beijing key laboratory of nasal diseases, Beijing Institute of Otolaryngology, Beijing, PR China
| | - Tim Meese
- NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
| | - Sharon Van Nevel
- Upper Airway Research Laboratory, Ghent University, Ghent, Belgium
| | | | - Stijn Vanhee
- Upper Airway Research Laboratory, Ghent University, Ghent, Belgium; VIB-UGent, Center for Inflammation Research, Gent 9052, Belgium
| | - Barbara M Bröker
- Institute of Immunology, University Medicine Greifswald, Greifswald, Germany
| | - Zhengqi Li
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China
| | - Ellen de Meester
- NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
| | - Natalie De Ruyck
- Upper Airway Research Laboratory, Ghent University, Ghent, Belgium
| | - Thibaut Van Zele
- Upper Airway Research Laboratory, Ghent University, Ghent, Belgium
| | - Philip Gevaert
- Upper Airway Research Laboratory, Ghent University, Ghent, Belgium
| | - Filip Van Nieuwerburgh
- NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
| | - Luo Zhang
- Department of Allergy, Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, PR China; Beijing key laboratory of nasal diseases, Beijing Institute of Otolaryngology, Beijing, PR China
| | - Mohamed H Shamji
- National Heart and Lung Institute, Imperial College London, and NIHR Imperial Biomedical Research Centre, United Kingdom
| | - Weiping Wen
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China; The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China.
| | - Nan Zhang
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China; Upper Airway Research Laboratory, Ghent University, Ghent, Belgium.
| | - Claus Bachert
- The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Department of Otorhinolaryngology, International Airway Research Center, Guangzhou, China; Upper Airway Research Laboratory, Ghent University, Ghent, Belgium; Clinic for ENT diseases and head and neck surgery, University Clinic Münster, Münster, Germany; Division of ENT diseases, CLINTEC, Karolinska Institute, Stockholm, Sweden.
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17
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Jorgensen R, Gao H, Chandra S, Sundar V, Loy J, Van Antwerp C, Ng PKW, Gangur V. Chronic application of alcohol-soluble gluten extract over undamaged skin causes clinical sensitization for life-threatening anaphylaxis via activation of systemic Th2 immune responses in mice. FRONTIERS IN ALLERGY 2023; 4:1214051. [PMID: 37841051 PMCID: PMC10570422 DOI: 10.3389/falgy.2023.1214051] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 09/15/2023] [Indexed: 10/17/2023] Open
Abstract
Introduction Gluten allergy is a major public health problem that is growing at an alarming rate. Specific mechanisms underlying sensitization to gluten remain incompletely understood. Currently, it is unclear whether chronic exposure to alcohol-soluble gluten extract via undamaged skin has the capacity to clinically sensitize mice for life-threatening anaphylaxis. Using an adjuvant-free mouse model, here we tested the hypothesis that chronic application of alcohol-soluble durum gluten (ASDG) extract will clinically sensitize mice for life-threatening anaphylaxis. Methods This study was conducted in a gluten-free Balb/c mouse colony that was established and maintained on a plant protein-free diet. Groups of adult female mice were exposed dermally to ASDG extract or vehicle once a week for 9-weeks. Specific (s) and total (t) IgE levels were quantified. Mice were challenged systemically with ASDG to measure symptoms of systemic anaphylaxis. Hypothermic shock response (HSR) and mucosal mast cell degranulation response (MMCR) were determined upon challenge. Spleen Th1, Th2, and other immune markers were quantified. Results We found that chronic exposure to ASDG elicited robust elevation of sIgE and tIgE. Systemic challenge with ASDG, but not vehicle, elicited life-threatening anaphylaxis associated with dramatic HSR and MMCR. Correlation analysis demonstrated direct positive inter-relationships among IgE, HSR, and MMCR. Anaphylaxis was associated with significant elevation of prototypic Th2 but not Th1 immune markers in the spleen. Discussion/Conclusion Our study collectively demonstrates that ASDG is intrinsically allergenic; and chronic exposure to ASDG via undamaged skin can clinically sensitize mice for life-threatening anaphylaxis via activating the systemic Th2 immune responses.
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Affiliation(s)
- Rick Jorgensen
- Food Allergy and Immunology Laboratory, Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States
| | - Haoran Gao
- Food Allergy and Immunology Laboratory, Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States
| | - Shivam Chandra
- Food Allergy and Immunology Laboratory, Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States
| | - Vaisheswini Sundar
- Food Allergy and Immunology Laboratory, Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States
| | - Jaden Loy
- Food Allergy and Immunology Laboratory, Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States
| | - Chris Van Antwerp
- Food Allergy and Immunology Laboratory, Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States
| | - Perry K. W. Ng
- Cereal Science Laboratory, Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States
| | - Venu Gangur
- Food Allergy and Immunology Laboratory, Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States
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Li H, Yang W, Li H, Bai X, Zhang H, Fan W, Liu W, Sun L. PROTAC targeting cyclophilin A controls virus-induced cytokine storm. iScience 2023; 26:107535. [PMID: 37636080 PMCID: PMC10448112 DOI: 10.1016/j.isci.2023.107535] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 07/22/2023] [Accepted: 07/28/2023] [Indexed: 08/29/2023] Open
Abstract
Cytokine storms caused by viruses are associated with elevated cytokine levels and uncontrolled inflammatory responses that can lead to acute respiratory distress syndrome. Current antiviral therapies are not sufficient to prevent or treat these complications. Cyclophilin A (CypA) is a key factor that regulates the production of multiple cytokines and could be a potential therapeutic target for cytokine storms. Here, three proteolysis targeting chimeras (PROTACs) targeting CypA were designed. These PROTACs bind to CypA, enhance its ubiquitination, and promote its degradation in both cell lines and mouse organs. During influenza B virus (IBV) infection, PROTAC-mediated CypA depletion reduces P65 phosphorylation and NF-κB-mediated proinflammatory cytokine production in A549 cells. Moreover, Comp-K targeting CypA suppresses excessive secretion of proinflammatory cytokines in bronchoalveolar lavage fluid, reduces lung injury, and enhances survival rates of IBV-infected mice. Collectively, we provide PROTACs targeting CypA, which are potential candidates for the control of cytokine storms.
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Affiliation(s)
- Heqiao Li
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518107, China
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wenxian Yang
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518107, China
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Huizi Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaoyuan Bai
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518107, China
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - He Zhang
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518107, China
| | - Wenhui Fan
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Wenjun Liu
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518107, China
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lei Sun
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
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19
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Yuan J. CCR2: A characteristic chemokine receptor in normal and pathological intestine. Cytokine 2023; 169:156292. [PMID: 37437448 DOI: 10.1016/j.cyto.2023.156292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/25/2023] [Accepted: 07/01/2023] [Indexed: 07/14/2023]
Abstract
C-C motif chemokine receptor 2 (CCR2), together with its ligands, especially C-C motif ligand 2 (CCL2), to which CCR2 has the highest affinity, form a noteworthy signaling pathway in recruiting macrophages for the immune responses among variegated disorders in vivo environment. Scientometric methods are used to analyze intestine-related CCR2 expression. We describe the current knowledge on biological function of CCR2 in physiological intestine in three dimensions, namely its effects on stromal cells, angiogenesis, and remodeling. However, anomalous expression of CCR2 has also been conveyed to correlate with detrimental outcomes in intestine, such as infective colitis, inflammatory bowel disease, carcinogenesis, and colon-related metastasis. In this article, we briefly summarize recent experimental works on CCR2 and its ligands, mostly CCL2, in intestinal-related physiological and pathological states to ravel out their working mechanisms in intestinal diseases.
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Affiliation(s)
- Jin Yuan
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China.
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20
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Chen Z, Li C, Yu J. Monocyte chemoattractant protein-1 as a potential marker for patients with sepsis: a systematic review and meta-analysis. Front Med (Lausanne) 2023; 10:1217784. [PMID: 37720514 PMCID: PMC10502711 DOI: 10.3389/fmed.2023.1217784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 08/17/2023] [Indexed: 09/19/2023] Open
Abstract
Objective To investigate the diagnostic value of monocyte chemoattractant protein-1 (MCP-1) as a biomarker for adult patients with sepsis. Methods Related studies on the diagnostic value of MCP-1 in adult patients with sepsis were searched in PubMed, Cochrane Library, Embase, CNKI, CBM, Web of Science, Scopus, and Wanfang Data databases (published to February 20, 2023) was performed if studies assessed the diagnostic accuracy of MCP-1 in adult patients with sepsis and provided appropriate information sufficient to construct a 2 × 2 linked table, studies were included. Results Data from 8 studies with a total of 805 patients were included. The combined sensitivity was 0.84 (95% CI 0.70-0.92), the specificity was 0.82 (95% CI 0.67-0.91), the combined positive likelihood ratio was 3.711 (2.119-6.500), the negative likelihood ratio was 0.287 (0.198-0.415), and the area under the working characteristic curve for combined subjects was 0.88. The diagnostic odds ratio (DOR) was 16.508 (7.632-35.706). Meta-regression analysis showed that the results were not significant. Deeks' funnel plot showed that there was no publication bias. Conclusion According to our meta-analysis, MCP-1 is a valuable biomarker and may provide evidence for the diagnosis of sepsis in adults.
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Affiliation(s)
- Zhuo Chen
- Department of Intensive Care Unit, The Second Hospital of Dalian Medical University, Dalian, China
| | - Chenwei Li
- Department of Pulmonary and Critical Care Medicine, The Second Hospital of Dalian Medical University, Dalian, China
| | - Jian Yu
- Department of Intensive Care Unit, The Second Hospital of Dalian Medical University, Dalian, China
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21
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Fang Y, Jin W, Guo Z, Hao J. Quercetin Alleviates Asthma-Induced Airway Inflammation and Remodeling through Downregulating Periostin via Blocking TGF-β1/Smad Pathway. Pharmacology 2023; 108:432-443. [PMID: 37343534 DOI: 10.1159/000530703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 04/10/2023] [Indexed: 06/23/2023]
Abstract
INTRODUCTION The aim of the study was to discuss whether the anti-asthmatic effect of quercetin is related to periostin and the downstream molecular pathway of quercetin's anti-asthmatic effect. METHODS We constructed asthmatic mice, sensitized by ovalbumin, and administrated different treatments into mice according to the experimental design. In this study, we mainly observed the inflammatory response, airway fibrosis, and airway hyperresponsiveness in asthmatic mice. Pathological stains (H&E, PAS, and Masson) were performed. We also detected the inflammation factors and fibrosis-related cytokines by enzyme-linked immunosorbent serologic assay. In addition, we also explored the level of periostin by enzyme-linked immunosorbent serologic assay and Western blot. At the same time, TGF-β1/Smad pathway was also determined by Western blot. RESULTS A high expression of periostin was found in asthmatic mice, and quercetin decreases periostin content in bronchoalveolar lavage fluid. Quercetin and OC-20 inhibit airway inflammation response, airway fibrosis, and airway hyperreactivity. Quercetin downregulated TGF-β1/Smad pathway in the lung tissues of asthmatic mice. Anti-asthma role of quercetin is related to periostin. Then deeper mechanical study revealed that inhibiting TGF-β1 could improve asthmatic symptoms, and quercetin exerted the protective effect on asthmatic mice through inhibition of TGF-β1/Smad pathway. CONCLUSION Quercetin provided a protective role against asthma via periostin, manifested by mild inflammatory infiltration, reduced goblet cell proliferation, and reduced airway fibrosis. TGF-β1/Smad pathway is an important transduction system, participating in the protective effect of quercetin on asthma.
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Affiliation(s)
- Yanni Fang
- Department of Pediatrics, Yantaishan Hospital, Yantai, China
| | - Wenwen Jin
- Department of Clinical Laboratory, Yantai Yuhuangding Hospital, Yantai, China
| | - Zhen Guo
- Department of Pediatrics, Yantaishan Hospital, Yantai, China
| | - Jumei Hao
- Department of Pediatrics, Yantaishan Hospital, Yantai, China
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22
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Alladina J, Smith NP, Kooistra T, Slowikowski K, Kernin IJ, Deguine J, Keen HL, Manakongtreecheep K, Tantivit J, Rahimi RA, Sheng SL, Nguyen ND, Haring AM, Giacona FL, Hariri LP, Xavier RJ, Luster AD, Villani AC, Cho JL, Medoff BD. A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma. Sci Immunol 2023; 8:eabq6352. [PMID: 37146132 PMCID: PMC10440046 DOI: 10.1126/sciimmunol.abq6352] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 04/13/2023] [Indexed: 05/07/2023]
Abstract
Asthma is a chronic disease most commonly associated with allergy and type 2 inflammation. However, the mechanisms that link airway inflammation to the structural changes that define asthma are incompletely understood. Using a human model of allergen-induced asthma exacerbation, we compared the lower airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA sequencing. In response to allergen, the asthmatic airway epithelium was highly dynamic and up-regulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls. IL9-expressing pathogenic TH2 cells were specific to asthmatic airways and were only observed after allergen challenge. Additionally, conventional type 2 dendritic cells (DC2 that express CD1C) and CCR2-expressing monocyte-derived cells (MCs) were uniquely enriched in asthmatics after allergen, with up-regulation of genes that sustain type 2 inflammation and promote pathologic airway remodeling. In contrast, allergic controls were enriched for macrophage-like MCs that up-regulated tissue repair programs after allergen challenge, suggesting that these populations may protect against asthmatic airway remodeling. Cellular interaction analyses revealed a TH2-mononuclear phagocyte-basal cell interactome unique to asthmatics. These pathogenic cellular circuits were characterized by type 2 programming of immune and structural cells and additional pathways that may sustain and amplify type 2 signals, including TNF family signaling, altered cellular metabolism, failure to engage antioxidant responses, and loss of growth factor signaling. Our findings therefore suggest that pathogenic effector circuits and the absence of proresolution programs drive structural airway disease in response to type 2 inflammation.
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Affiliation(s)
- Jehan Alladina
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Neal P. Smith
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Tristan Kooistra
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Kamil Slowikowski
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Isabela J. Kernin
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Jacques Deguine
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Henry L. Keen
- Iowa Institute of Human Genetics, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Kasidet Manakongtreecheep
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Jessica Tantivit
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Rod A. Rahimi
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Susan L. Sheng
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Nhan D. Nguyen
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Alexis M. Haring
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Francesca L. Giacona
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lida P. Hariri
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Ramnik J. Xavier
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Andrew D. Luster
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Alexandra-Chloé Villani
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Josalyn L. Cho
- Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Benjamin D. Medoff
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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23
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Squillaci D, Marcuzzi A, Rimondi E, Riccio G, Barbi E, Zanon D, Maximova N. Defibrotide impact on the acute GVHD disease incidence in pediatric hematopoietic stem cell transplant recipients. Life Sci Alliance 2023; 6:e202201786. [PMID: 36878639 PMCID: PMC9990457 DOI: 10.26508/lsa.202201786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 02/25/2023] [Accepted: 02/27/2023] [Indexed: 03/08/2023] Open
Abstract
Despite advances in acute graft-versus-host disease (aGVHD) prophylaxis, current pharmacological approaches fail to prevent aGVHD. The protective effect of defibrotide on GVHD incidence and GVHD-free survival has not been sufficiently studied. 91 pediatric patients included in this retrospective study were divided into two groups based on defibrotide use. We compared the incidence of aGVHD and chronic GVHD-free survival between the defibrotide and control groups. The incidence and severity of aGVHD were significantly lower in patients who received defibrotide prophylactic administration than in the control group. This improvement was observed in the liver and intestinal aGVHD. No defibrotide prophylaxis benefit was observed in the prevention of chronic GVHD. The pro-inflammatory cytokine levels were significantly higher in the control group. Our findings suggest that prophylactic administration of defibrotide in pediatric patients significantly reduces the incidence and severity of aGVHD, with a modification of cytokine pattern, both strongly coherent with the protective drug's action. This evidence adds to pediatric retrospective studies and preclinical data suggesting a possible defibrotide role in this setting.
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Affiliation(s)
- Domenica Squillaci
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Annalisa Marcuzzi
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Erika Rimondi
- Department of Translational Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Guglielmo Riccio
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Egidio Barbi
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
- Department of Pediatrics, Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy
| | - Davide Zanon
- Department of Pediatrics, Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy
| | - Natalia Maximova
- Department of Pediatrics, Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy
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24
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Verçosa BLA, Muniz-Junqueira MI, Menezes-Souza D, Fujiwara RT, Borges LDF, Melo MN, Vasconcelos AC. MCP-1/IL-12 ratio expressions correlated with adventitial collagen depositions in renal vessels and IL-4/IFN-γ expression correlated with interstitial collagen depositions in the kidneys of dogs with canine leishmaniasis. Mol Immunol 2023; 156:61-76. [PMID: 36889187 DOI: 10.1016/j.molimm.2023.02.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/04/2023] [Accepted: 02/13/2023] [Indexed: 03/08/2023]
Abstract
Collagen deposition is a common event in chronic inflammation, and canine Leishmaniosis (CanL) is generally associated with a long and chronic evolution. Considering that the kidney shows fibrinogenic changes during CanL, and the balance of cytokines/chemokines regulates the profibrinogenic and antifibrinogenic immune responses differently, it can be hypothesized that the balance of cytokines/chemokines can be differentially expressed in the renal tissue in order to determine the expression of collagen depositions in the kidneys. This study aimed to measure collagen deposition and to evaluate cytokine/chemokine expressions in the kidney by means of qRT-PCR in sixteen Leishmania-infected dogs and six uninfected controls. Kidney fragments were stained with hematoxylin & eosin (H&E), Masson's Trichrome, Picrosirius Red, and Gomori's reticulin. Intertubular and adventitial collagen depositions were evaluated by the morphometric approach. Cytokine RNA expressions were measured by means of qRT-PCR to identify molecules involved in chronic collagen depositions in kidneys with CanL. Collagen depositions were related to the presence of clinical signs, and more intense intertubular collagen depositions occurred in infected dogs. Adventitial collagen deposition, as morphometrically measured by the average area of the collagen, was more intense in clinically affected dogs than in subclinically infected dogs. TNF-α/TGF-β, MCP1/IL-12, CCL5/IL-12, IL-4/IFN-γ, and IL-12/TGF-β expressions were associated with clinical manifestations in dogs with CanL. The IL-4/IFN-α ratio was more commonly expressed and upregulated in clinically affected dogs, and downregulated in subclinically infected dogs. Furthermore, MCP-1/IL-12 and CCL5/IL-12 were more commonly expressed in subclinically infected dogs. Strong positive correlations were detected between morphometric values of interstitial collagen depositions and MCP-1/IL-12, IL-12, and IL-4 mRNA expression levels in the renal tissues. Adventitial collagen deposition was correlated with TGF-β, IL-4/IFN-γ, and TNF-α/TGF-β. In conclusion, our results showed the association of MCP-1/IL-12 and CCL5/IL-12 ratios with an absence of clinical signs, as well as an IL-4/IFN-α ratio with adventitial and intertubular collagen depositions in dogs with visceral leishmaniosis.
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Affiliation(s)
- Barbara Laurice Araújo Verçosa
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Imunologia Celular, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil.
| | | | - Daniel Menezes-Souza
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Ricardo Toshio Fujiwara
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Luciano de F Borges
- Instituto de Ciências Biológicas, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Maria Norma Melo
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Anilton Cesar Vasconcelos
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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25
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Sun X, Hosomi K, Shimoyama A, Yoshii K, Lan H, Wang Y, Yamaura H, Nagatake T, Ishii KJ, Akira S, Kiyono H, Fukase K, Kunisawa J. TLR4 agonist activity of Alcaligenes lipid a utilizes MyD88 and TRIF signaling pathways for efficient antigen presentation and T cell differentiation by dendritic cells. Int Immunopharmacol 2023; 117:109852. [PMID: 36806039 DOI: 10.1016/j.intimp.2023.109852] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 01/18/2023] [Accepted: 02/04/2023] [Indexed: 02/22/2023]
Abstract
Alcaligenes faecalis was previously identified as an intestinal lymphoid tissue-resident commensal bacteria, and our subsequent studies showed that lipopolysaccharide and its core active element (i.e., lipid A) have a potent adjuvant activity to promote preferentially antigen-specific Th17 response and antibody production. Here, we compared A. faecalis lipid A (ALA) with monophosphoryl lipid A, a licensed lipid A-based adjuvant, to elucidate the immunological mechanism underlying the adjuvant properties of ALA. Compared with monophosphoryl lipid A, ALA induced higher levels of MHC class II molecules and costimulatory CD40, CD80, and CD86 on dendritic cells (DCs), which in turn resulted in strong T cell activation. Moreover, ALA more effectively promoted the production of IL-6 and IL-23 from DCs than did monophosphoryl lipid A, thus leading to preferential induction of Th17 and Th1 cells. As underlying mechanisms, we found that the ALA-TLR4 axis stimulated both MyD88- and TRIF-mediated signaling pathways, whereas monophosphoryl lipid A was biased toward TRIF signaling. These findings revealed the effects of ALA on DCs and T cells and its induction pattern on signaling pathways.
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Affiliation(s)
- Xiao Sun
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
| | - Koji Hosomi
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
| | - Atsushi Shimoyama
- Graduate School of Science, Osaka University, Osaka, Japan; Collaborative Research between NIBIOHN and Graduate School of Science, Forefront Research Center, Osaka University, Osaka, Japan
| | - Ken Yoshii
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Huangwenxian Lan
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
| | - Yunru Wang
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
| | - Haruki Yamaura
- Graduate School of Science, Osaka University, Osaka, Japan
| | - Takahiro Nagatake
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Laboratory of Functional Anatomy, Department of Life Sciences, School of Agriculture, Meiji University, Kanagawa, Japan
| | - Ken J Ishii
- International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Immunology Frontier Research Center, Osaka University, Osaka, Japan; Center for Vaccine and Adjuvant Research (CVAR), National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
| | - Shizuo Akira
- Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Hiroshi Kiyono
- International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), San Diego, CA, United States; Chiba University (CU)-UCSD Center for Mucosal Immunology, Allergy and Vaccines (cMAV), UCSD, San Diego, CA, United States; Future Medicine Education and Research Organization, Chiba University, Chiba, Japan; Department of Human Mucosal Vaccinology, Chiba University Hospital, Chiba, Japan; Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Koichi Fukase
- Graduate School of Science, Osaka University, Osaka, Japan; Collaborative Research between NIBIOHN and Graduate School of Science, Forefront Research Center, Osaka University, Osaka, Japan
| | - Jun Kunisawa
- Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, Collaborative Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan; Graduate School of Science, Osaka University, Osaka, Japan; Collaborative Research between NIBIOHN and Graduate School of Science, Forefront Research Center, Osaka University, Osaka, Japan; Graduate School of Medicine, Osaka University, Osaka, Japan; International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Kobe, Japan; Research Organization for Nano and Life Innovation, Waseda University, Tokyo, Japan; Graduate School of Dentistry, Osaka University, Suita, Japan.
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26
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Graves' disease induced by IFN-β1a therapy: A case report, review of literature and new insights into the pathogenesis. Autoimmun Rev 2023; 22:103238. [PMID: 36436749 DOI: 10.1016/j.autrev.2022.103238] [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: 10/09/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022]
Abstract
Since 1997, when the first case of autoimmune hyperthyroidism induced by Interferon (IFN)-β1b therapy was described, we know about the risk of thyroid dysfunction related to this treatment, particularly in patients with preexisting thyroid autoimmune disorders (AITD). A 60-year-old female, with a 15-year history of euthyroid autoimmune thyroiditis and a 3-year history of Multiple Sclerosis (MS), was admitted to our department for the evaluation of hyperthyroidism. Twenty months before, she had started specific immunomodulant IFN-β1a therapy (30 μg/week). At the first visit, the patient complained tachycardia, weight loss, blurry vision with swollen eyes and excessive lacrimation; thyroid tests showed hyperthyroidism with positive TSH-receptor-autoantibodies. Further evaluation with orbit Magnetic Resonance Imaging (MRI) revealed bilaterally mild enlargement of the extraocular muscles, supporting the suspect of Graves' ophthalmopathy (GO). To our knowledge, this is the first report of Graves' disease (GD) and ophthalmopathy associated with IFN-β1a treatment in a patient with MS. Furthermore, this case could open new interesting knowledge behind GD immunopathogenesis.
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Genetic Iron Overload Hampers Development of Cutaneous Leishmaniasis in Mice. Int J Mol Sci 2023; 24:ijms24021669. [PMID: 36675185 PMCID: PMC9864902 DOI: 10.3390/ijms24021669] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
The survival, growth, and virulence of Leishmania spp., a group of protozoan parasites, depends on the proper access and regulation of iron. Macrophages, Leishmania's host cell, may divert iron traffic by reducing uptake or by increasing the efflux of iron via the exporter ferroportin. This parasite has adapted by inhibiting the synthesis and inducing the degradation of ferroportin. To study the role of iron in leishmaniasis, we employed Hjv-/- mice, a model of hemochromatosis. The disruption of hemojuvelin (Hjv) abrogates the expression of the iron hormone hepcidin. This allows unrestricted iron entry into the plasma from ferroportin-expressing intestinal epithelial cells and tissue macrophages, resulting in systemic iron overload. Mice were injected with Leishmania major in hind footpads or intraperitoneally. Compared with wild-type controls, Hjv-/- mice displayed transient delayed growth of L. major in hind footpads, with a significant difference in parasite burden 4 weeks post-infection. Following acute intraperitoneal exposure to L. major, Hjv-/- peritoneal cells manifested increased expression of inflammatory cytokines and chemokines (Il1b, Tnfa, Cxcl2, and Ccl2). In response to infection with L. infantum, the causative agent of visceral leishmaniasis, Hjv-/- and control mice developed similar liver and splenic parasite burden despite vastly different tissue iron content and ferroportin expression. Thus, genetic iron overload due to hemojuvelin deficiency appears to mitigate the early development of only cutaneous leishmaniasis.
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Lin Z, Shi JL, Chen M, Zheng ZM, Li MQ, Shao J. CCL2: An important cytokine in normal and pathological pregnancies: A review. Front Immunol 2023; 13:1053457. [PMID: 36685497 PMCID: PMC9852914 DOI: 10.3389/fimmu.2022.1053457] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 12/12/2022] [Indexed: 01/07/2023] Open
Abstract
C-C motif ligand 2 (CCL2), also known as monocytic chemotactic protein 1 (MCP-1), is an integral chemotactic factor which recruits macrophages for the immune response. Together with its receptors (e.g., CCR2, ACKR1, and ACKR2), they exert noticeable influences on various diseases of different systems. At the maternal-fetal interface, CCL2 is detected to be expressed in trophoblasts, decidual tissue, the myometrium, and others. Meanwhile, existing reports have determined a series of physiological regulators of CCL2, which functions in maintaining normal recruitment of immunocytes, tissue remodeling, and angiogenesis. However, abnormal levels of CCL2 have also been reported to be associated with adverse pregnancy outcomes such as spontaneous abortion, preeclampsia and preterm labor. In this review, we concentrate on CCL2 expression at the maternal-fetal interface, as well as its precise regulatory mechanisms and classic signaling pathways, to reveal the multidimensional aspects of CCL2 in pregnancy.
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Affiliation(s)
- Zhi Lin
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
| | - Jia-Lu Shi
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
| | - Min Chen
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
| | - Zi-Meng Zheng
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
| | - Ming-Qing Li
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
- National Health Commision (NHC) Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Jun Shao
- Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
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Pathogenic Th2 Cytokine Profile Skewing by IFN-γ-Responding Vitiligo Fibroblasts via CCL2/CCL8. Cells 2023; 12:cells12020217. [PMID: 36672151 PMCID: PMC9856695 DOI: 10.3390/cells12020217] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/31/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
PURPOSE Vitiligo is a T cell-mediated skin depigmentation disease. Though treatments arresting disease progression and inducing repigmentation are available, the efficacy of these options is often limited and poorly sustained. How stromal signals contribute to the interferon-γ-dominant skin niches is unclear. This study aims to determine how fibroblasts participate in the IFN-γ-dominant vitiligo niche. PATIENTS AND METHODS Mouse vitiligo models were established. Fibroblasts from control and vitiligo mice were extracted for RNA sequencing. In vitro IFN-γ stimulation was performed to verify the JAK-STAT pathway by qPCR and Western blot. T cell polarization with chemokines was measured by flow cytometry. Protein levels in tissues were also examined by IHC. RESULTS The vitiligo mouse model recapitulates the human CD8-IFN-γ pathway. RNA sequencing revealed elevated chemokine CCL2 and CCL8 in vitiligo fibroblast, which may be regulated by the JAK-STAT signaling. Such phenomenon is verified by JAK inhibitor peficitinib in vitro. Moreover, CCL2 addition into the naïve T polarization system promoted type 2 cytokines secretion, which represents a hallmark of vitiligo lesions. CONCLUSION Dermal fibroblasts, a principal constituent of skin structure, respond to IFN-γ by skewing T cells towards a type 2 cytokine profile via CCL2 and CCL8, which can be abrogated by JAK inhibitor peficitinib.
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Esnault S, Jarjour NN. Development of Adaptive Immunity and Its Role in Lung Remodeling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1426:287-351. [PMID: 37464127 DOI: 10.1007/978-3-031-32259-4_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
Asthma is characterized by airflow limitations resulting from bronchial closure, which can be either reversible or fixed due to changes in airway tissue composition and structure, also known as remodeling. Airway remodeling is defined as increased presence of mucins-producing epithelial cells, increased thickness of airway smooth muscle cells, angiogenesis, increased number and activation state of fibroblasts, and extracellular matrix (ECM) deposition. Airway inflammation is believed to be the main cause of the development of airway remodeling in asthma. In this chapter, we will review the development of the adaptive immune response and the impact of its mediators and cells on the elements defining airway remodeling in asthma.
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Comins-Boo A, Valdeolivas L, Pérez-Pla F, Cristóbal I, Subhi-Issa N, Domínguez-Soto Á, Pilar-Suárez L, Gasca-Escorial P, Calvo-Urrutia M, Fernández-Arquero M, Herráiz MÁ, Corbí Á, Sánchez-Ramón S. Immunophenotyping of peripheral blood monocytes could help identify a baseline pro-inflammatory profile in women with recurrent reproductive failure. J Reprod Immunol 2022; 154:103735. [PMID: 36063657 DOI: 10.1016/j.jri.2022.103735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 07/23/2022] [Accepted: 08/19/2022] [Indexed: 12/14/2022]
Abstract
Recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) are two well-defined clinical entities, but the role of the monocytes in their pathophysiology needs to be clarified. This study aimed to evaluate the role of the three monocyte subsets (classical, intermediate, and non-classical) and relevant cytokines/chemokines in a cohort of RPL and RIF women to better characterize a baseline proinflammatory profile that could define inflammatory pathophysiology in these two different conditions. We evaluated 108 non-pregnant women: 53 RPL, 24 RIF, and 31 fertile healthy controls (HC). Multiparametric flow cytometry was used to quantify the frequency of surface chemokine receptors (CCR2, CCR5, and CX3CR1) on the monocyte subsets. Cytokines were assessed in plasma samples using a multiplex assay. The CX3CR1+ and CCR5+ intermediate monocytes were significantly higher in RPL and RIF compared to HC. A significant positive correlation was observed between CX3CR1+ intermediate monocytes and IL-17A (P = .03, r = 0.43). The Boruta algorithm followed by a multivariate logistic regression model was used to select the most relevant variables that could help define RPL and RIF: in RPL were CX3CR1 non-classical monocytes, TGF-β1, and CCR5 intermediate monocytes; in RIF: CCR5 intermediate monocytes and TGF-β3. The combination of these variables could predict RPL and RIF with 90 % and 82 %, respectively. Our study suggests that a combination of specific blood monocyte subsets and cytokines could aid in identifying RPL and RIF women with a pro-inflammatory profile. These findings could provide a more integrated understanding of these pathologies. Further investigation and validation in independent cohorts are warranted.
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Affiliation(s)
- Alejandra Comins-Boo
- Department of Immunology, IML, and IdSSC, Hospital Clínico San Carlos, Madrid, Spain; Department of Immunology, Ophthalmology, and ENT, School of Medicine, Complutense University School of Medicine, Madrid, Spain
| | - Lorena Valdeolivas
- Department of Immunology, IML, and IdSSC, Hospital Clínico San Carlos, Madrid, Spain; Department of Immunology, Ophthalmology, and ENT, School of Medicine, Complutense University School of Medicine, Madrid, Spain
| | - Fernando Pérez-Pla
- Department of Applied Mathematics and Computational Science, University of Cantabria, Spain
| | - Ignacio Cristóbal
- Department of Obstetrics and Gynecology, Hospital Clínico San Carlos, Madrid, Spain
| | - Nabil Subhi-Issa
- Department of Immunology, IML, and IdSSC, Hospital Clínico San Carlos, Madrid, Spain; Department of Immunology, Ophthalmology, and ENT, School of Medicine, Complutense University School of Medicine, Madrid, Spain
| | - Ángeles Domínguez-Soto
- Molecular Microbiology and Infection Biology Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
| | - Lydia Pilar-Suárez
- Department of Obstetrics and Gynecology, Hospital Clínico San Carlos, Madrid, Spain
| | - Pilar Gasca-Escorial
- Department of Obstetrics and Gynecology, Hospital Clínico San Carlos, Madrid, Spain
| | - Marta Calvo-Urrutia
- Department of Obstetrics and Gynecology, Hospital Clínico San Carlos, Madrid, Spain
| | - Miguel Fernández-Arquero
- Department of Immunology, IML, and IdSSC, Hospital Clínico San Carlos, Madrid, Spain; Department of Immunology, Ophthalmology, and ENT, School of Medicine, Complutense University School of Medicine, Madrid, Spain
| | - Miguel Ángel Herráiz
- Department of Obstetrics and Gynecology, Hospital Clínico San Carlos, Madrid, Spain
| | - Ángel Corbí
- Molecular Microbiology and Infection Biology Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
| | - Silvia Sánchez-Ramón
- Department of Immunology, IML, and IdSSC, Hospital Clínico San Carlos, Madrid, Spain; Department of Immunology, Ophthalmology, and ENT, School of Medicine, Complutense University School of Medicine, Madrid, Spain.
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Ranjbar M, Rahimi A, Baghernejadan Z, Ghorbani A, Khorramdelazad H. Role of CCL2/CCR2 axis in the pathogenesis of COVID-19 and possible Treatments: All options on the Table. Int Immunopharmacol 2022; 113:109325. [PMID: 36252475 PMCID: PMC9561120 DOI: 10.1016/j.intimp.2022.109325] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 10/05/2022] [Accepted: 10/05/2022] [Indexed: 11/05/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is cause of the novel coronavirus disease (COVID-19). In the last two years, SARS-CoV-2 has infected millions of people worldwide with different waves, resulting in the death of many individuals. The evidence disclosed that the host immune responses to SARS-CoV-2 play a pivotal role in COVID-19 pathogenesis and clinical manifestations. In addition to inducing antiviral immune responses, SARS-CoV-2 can also cause dysregulated inflammatory responses characterized by the noticeable release of proinflammatory mediators in COVID-19 patients. Among these proinflammatory mediators, chemokines are considered a subset of cytokines that participate in the chemotaxis process to recruit immune and non-immune cells to the site of inflammation and infection. Researchers have demonstrated that monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor (CCR2) are involved in the recruitment of monocytes and infiltration of these cells into the lungs of patients suffering from COVID-19. Moreover, elevated levels of CCL2 have been reported in the bronchoalveolar lavage fluid (BALF) obtained from patients with severe COVID-19, initiating cytokine storm and promoting CD163+ myeloid cells infiltration in the airways and further alveolar damage. Therefore, CCL2/CCR axis plays a key role in the immunopathogenesis of COVID-19 and targeted therapy of involved molecules in this axis can be a potential therapeutic approach for these patients. This review discusses the biology of the CCL2/CCR2 axis as well as the role of this axis in COVID-19 immunopathogenesis, along with therapeutic options aimed at inhibiting CCL2/CCR2 and modulating dysregulated inflammatory responses in patients with severe SARS-CoV-2 infection.
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Affiliation(s)
- Mitra Ranjbar
- Department of Infectious Disease, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zeinab Baghernejadan
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Atousa Ghorbani
- Department of Biology, East Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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Angrand L, Masson JD, Rubio-Casillas A, Nosten-Bertrand M, Crépeaux G. Inflammation and Autophagy: A Convergent Point between Autism Spectrum Disorder (ASD)-Related Genetic and Environmental Factors: Focus on Aluminum Adjuvants. TOXICS 2022; 10:toxics10090518. [PMID: 36136483 PMCID: PMC9502677 DOI: 10.3390/toxics10090518] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/19/2022] [Accepted: 08/25/2022] [Indexed: 05/10/2023]
Abstract
Autism spectrum disorder (ASD), schizophrenia, and bipolar disorder are genetically complex and heterogeneous neurodevelopmental disorders (NDDs) resulting from genetic factors and gene-environment (GxE) interactions for which onset occurs in early brain development. Recent progress highlights the link between ASD and (i) immunogenetics, neurodevelopment, and inflammation, and (ii) impairments of autophagy, a crucial neurodevelopmental process involved in synaptic pruning. Among various environmental factors causing risk for ASD, aluminum (Al)-containing vaccines injected during critical periods have received special attention and triggered relevant scientific questions. The aim of this review is to discuss the current knowledge on the role of early inflammation, immune and autophagy dysfunction in ASD as well as preclinical studies which question Al adjuvant impacts on brain and immune maturation. We highlight the most recent breakthroughs and the lack of epidemiological, pharmacokinetic and pharmacodynamic data constituting a "scientific gap". We propose additional research, such as genetic studies that could contribute to identify populations at genetic risk, improving diagnosis, and potentially the development of new therapeutic tools.
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Affiliation(s)
- Loïc Angrand
- Univ Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; (L.A.); (J.-D.M.)
- Ecole Nationale Vétérinaire d’Alfort IMRB, F-94700 Maisons-Alfort, France
- INSERM UMR-S 1270, 75005 Paris, France;
- Sorbonne Université, Campus Pierre et Marie Curie, 75005 Paris, France
- Institut du Fer à Moulin, 75005 Paris, France
| | - Jean-Daniel Masson
- Univ Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; (L.A.); (J.-D.M.)
- Ecole Nationale Vétérinaire d’Alfort IMRB, F-94700 Maisons-Alfort, France
| | - Alberto Rubio-Casillas
- Biology Laboratory, Autlán Regional Preparatory School, University of Guadalajara, Autlán 48900, Jalisco, Mexico;
- Autlán Regional Hospital, Health Secretariat, Autlán 48900, Jalisco, Mexico
| | - Marika Nosten-Bertrand
- INSERM UMR-S 1270, 75005 Paris, France;
- Sorbonne Université, Campus Pierre et Marie Curie, 75005 Paris, France
- Institut du Fer à Moulin, 75005 Paris, France
| | - Guillemette Crépeaux
- Univ Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; (L.A.); (J.-D.M.)
- Ecole Nationale Vétérinaire d’Alfort IMRB, F-94700 Maisons-Alfort, France
- Correspondence:
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Tai J, Kwak J, Han M, Kim TH. Different Roles of Dendritic Cells for Chronic Rhinosinusitis Treatment According to Phenotype. Int J Mol Sci 2022; 23:ijms23148032. [PMID: 35887379 PMCID: PMC9323853 DOI: 10.3390/ijms23148032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/20/2022] [Accepted: 07/20/2022] [Indexed: 02/01/2023] Open
Abstract
Dendritic cells (DCs) are antigen-presenting cells derived from the bone marrow that play an important role in the association between the innate and adaptive immune responses. The onset and development of chronic rhinosinusitis (CRS) involve a serious imbalance in immune regulation and mechanical dysfunction caused by an abnormal remodeling process. Recent studies have shown that an increase in DCs in CRS and their function of shaping the nasal mucosal immune response may play an important role in the pathogenesis of CRS. In this review, we discuss DC subsets in mice and humans, as well as the function of DCs in the nasal sinus mucosa. In addition, the mechanism by which DCs can be used as targets for therapeutic intervention for CRS and potential future research directions are also discussed.
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Affiliation(s)
- Junhu Tai
- Department of Otorhinolaryngology-Head & Neck Surgery, College of Medicine, Korea University, Seoul 02841, Korea; (J.T.); (J.K.); (M.H.)
| | - Jiwon Kwak
- Department of Otorhinolaryngology-Head & Neck Surgery, College of Medicine, Korea University, Seoul 02841, Korea; (J.T.); (J.K.); (M.H.)
| | - Munsoo Han
- Department of Otorhinolaryngology-Head & Neck Surgery, College of Medicine, Korea University, Seoul 02841, Korea; (J.T.); (J.K.); (M.H.)
- Mucosal Immunology Institute, College of Medicine, Korea University, Seoul 02841, Korea
| | - Tae Hoon Kim
- Department of Otorhinolaryngology-Head & Neck Surgery, College of Medicine, Korea University, Seoul 02841, Korea; (J.T.); (J.K.); (M.H.)
- Mucosal Immunology Institute, College of Medicine, Korea University, Seoul 02841, Korea
- Correspondence: ; Tel.: +82-02-920-5486
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Kimura S, Noguchi H, Yoshida K, Sato H, Nanbu U, Niino D, Shimajiri S, Nakayama T. Relationship of histamine expression with chemokine balance in the tumor microenvironment of squamous cell carcinoma of the tongue. Head Neck 2022; 44:1554-1562. [PMID: 35411649 DOI: 10.1002/hed.27056] [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: 11/21/2021] [Revised: 01/28/2022] [Accepted: 03/28/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Tumor-associated macrophages in the tumor microenvironment (TME), as a factor affecting lymphocytes, have received much attention. Both lymphocytes and macrophages can switch the expression of histamine receptors. In this study, we investigated the role of histamine in the TME of tongue squamous cell carcinoma (SCC). METHODS Sixty-seven patients with stage I tongue SCC were studied. Histamine was evaluated by the expression of L-histidine decarboxylase (HDC). Macrophages, T lymphocytes, and lymph vessel density, as well as the Ki-67 labeling index (LI) and depth of invasion (DOI), were compared with HDC expression. RESULTS HDC expression was significantly affected by the TME. The DOI, worst pattern of invasion, and Ki-67 LI were associated with histamine expression. C-C motif chemokine ligand (CCL) 2 and CCL22 were co-expressed with histamine H1 and H2 receptors. Histamine expression was most affected by the DOI. CONCLUSIONS Tongue SCC expressing histamine affected the TME via histamine receptors and chemokines.
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Affiliation(s)
- Satoshi Kimura
- Department of Clinical Pathology, Kitakyushu City Yahata Hospital, Kitakyushu, Japan.,Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hirotsugu Noguchi
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.,Department of Pathology, Field of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kosho Yoshida
- Department of Forensic Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hiroaki Sato
- Department of Forensic Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Uki Nanbu
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.,Department of Internal Medicine, National Hospital Organization Nagasaki Medical Center, Omura, Japan
| | - Daisuke Niino
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Shohei Shimajiri
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Toshiyuki Nakayama
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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Bernatowicz P, Pampuch A, Zywno H, Kowal K. Effect of Dermatophagoides pteronyssinus extract on the expression of genes involved in inflammation and tissue remodeling by peripheral blood mononuclear cells of allergic asthma patients. Adv Med Sci 2022; 67:234-240. [PMID: 35644064 DOI: 10.1016/j.advms.2022.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/20/2022] [Accepted: 05/17/2022] [Indexed: 11/30/2022]
Abstract
PURPOSE House dust mite allergy constitutes a risk factor for asthma development and is associated with a faster decline of lung function in allergic asthmatics (AAs). To evaluate the effect of Dermatophagoides pteronyssinus (Dp) allergens on the expression of genes involved in inflammation and tissue remodeling by peripheral blood mononuclear cells (PBMCs) isolated from the blood of AAs. MATERIALS AND METHODS The cells from AAs, allergic rhinitis without asthma patients (ARs), and healthy controls (HCs) were cultured in the presence of Dp, lipopolysaccharide (LPS), or without any stimulation. The expression of 84 genes was evaluated using a low-density microarray whereas, the quantitative expression analysis of selected genes was performed using a real-time polymerase chain reaction. The concentration of selected proteins in the cell culture supernatants was assessed using ELISA. RESULTS Stimulation of PBMCs with Dp and LPS resulted in a significant upregulation of 8 and 15 among 84 studied genes, respectively. The greatest upregulation was observed for CCL2 and CCL3 using Dp and LPS, respectively. In comparison with HCs, in AAs, significantly increased upregulation of CCL2 in response to Dp was found. The secretion of CCL2 and CCL3 by PBMCs reflected the pattern of gene expression at the mRNA level. The mean Dp-stimulated secretion of CCL2 by PBMCs of ARs was less than in AAs (p < 0.01), both being notably greater than in the HCs (p < 0.01). CONCLUSION Rapid and potent upregulation of CCL2 expression by PBMCs in response to Dp may constitute an important contribution to the development of allergic asthma.
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Affiliation(s)
- Pawel Bernatowicz
- Department of Hematology, Medical University of Bialystok, Bialystok, Poland
| | - Agnieszka Pampuch
- Department of Allergology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Hubert Zywno
- Department of Experimental Allergology and Immunology, Medical University of Bialystok, Bialystok, Poland
| | - Krzysztof Kowal
- Department of Allergology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland; Department of Experimental Allergology and Immunology, Medical University of Bialystok, Bialystok, Poland.
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Li WJ, Wu DW, Zhou YF, Zhang CW, Liao XW. Prognostic biomarker replication factor C subunit 5 and its correlation with immune infiltrates in acute myeloid leukemia. Hematology 2022; 27:555-564. [PMID: 35544695 DOI: 10.1080/16078454.2022.2072064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE To determine the role of replication factor C subunit 5 (RFC5) in acute myeloid leukemia (AML) from four aspects: expression, prognosis, biological functions, and its effects on the immune system. METHODS The RFC5 gene expression and survival analyses, biological function analyses including functional enrichment analysis of genes co-expressed with RFC5, RFC5-interacted gene network construction, gene set enrichment analysis (GSEA), and immune infiltration analysis were performed using data based on GDC TCGA and GEO. The CIBERSORT algorithm was employed to quantify immune cell fractions. All the statistical analyses were performed in SPSS software, GraphPad Prism, and R software. RESULTS RFC5 expression was abnormally expressed in AML (P <0.05). Notably, differential RFC5 expression was observed among different FAB AML subtypes and hematopoietic lineages (all P <0.05). More importantly, high RFC5 expression served as an independent prognostic factor for the poor overall survival of AML patients (P <0.001). Enrichment analyses revealed that RFC5 was involved in cell cycle-related pathways in AML. CIBERSORT analysis showed high proportions of M2 macrophages in the high RFC5 expression group. CONCLUSIONS RFC5 might serve as an effective and robust biomarker for the diagnosis and prognosis of AML. RFC5 might be involved in the AML progression via cell cycle regulation. Moreover, the correlation between RFC5 and immune cells might provide potential assistance for AML treatment.
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Affiliation(s)
- Wang-Jun Li
- Department of Pediatric Surgery, Wenzhou Medical University, Wenzhou, People's Republic of China.,Department of Pediatric Surgery, Lishui people's Hospital, Lishui, People's Republic of China
| | - Dong-Wei Wu
- Department of Pediatric Surgery, Lishui people's Hospital, Lishui, People's Republic of China
| | - Yi-Feng Zhou
- Department of Pediatric Surgery, Lishui people's Hospital, Lishui, People's Republic of China
| | - Chen-Wei Zhang
- Department of Pediatric Surgery, Lishui people's Hospital, Lishui, People's Republic of China
| | - Xiao-Wei Liao
- Department of Pediatric Surgery, Lishui people's Hospital, Lishui, People's Republic of China
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Kraemer L, McKay DM, Russo RC, Fujiwara RT. Chemokines and chemokine receptors: insights from human disease and experimental models of helminthiasis. Cytokine Growth Factor Rev 2022; 66:38-52. [DOI: 10.1016/j.cytogfr.2022.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 11/03/2022]
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Antimicrobial and Immunomodulatory Effects of Selected Chemokine and Antimicrobial Peptide on Cytokine Profile during Salmonella Typhimurium Infection in Mouse. Antibiotics (Basel) 2022; 11:antibiotics11050607. [PMID: 35625251 PMCID: PMC9137564 DOI: 10.3390/antibiotics11050607] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 02/05/2023] Open
Abstract
The antimicrobial and immunomodulatory capacities of the peptide Css54 and the chemokine MCP-1 were tested. The first, a peptide isolated from the venom of the scorpion Centruroides suffusus suffusus was synthesized chemically. In contrast, the second is a monocyte chemoattractant expressed as a recombinant protein in our lab. It was observed in vitro that Css54 inhibited the growth of Salmonella enterica serovar Typhimurium (6.2 µg/mL). At high concentrations, it was toxic to macrophages (25 µg/mL), activated macrophage phagocytosis (1.5 µg/mL), and bound Salmonella LPS (3 µg/mL). On the other hand, the recombinant MCP-1 neither inhibited the growth of Salmonella Typhimurium nor was it toxic to macrophages (up to 25 µg/mL), nor activated macrophage phagocytosis or bound Salmonella LPS (up to 3 µg/mL). Although it was observed in vivo in mice Balb/C that both Css54 and MCP-1 did not resolve the intraperitoneal infection by S. Typhimurium, Css54 decreased the expression of IL-6 and increased IL-10, IL-12p70, and TNF-α levels; meanwhile, MCP-1 decreased the expression of IFN-γ and increased IL-12p70 and TNF-α. It was also observed that the combination of both molecules Css54 and MCP-1 increased the expression of IL-10 and TNF-α.
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40
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Crosstalk between β-Catenin and CCL2 Drives Migration of Monocytes towards Glioblastoma Cells. Int J Mol Sci 2022; 23:ijms23094562. [PMID: 35562953 PMCID: PMC9101913 DOI: 10.3390/ijms23094562] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 02/06/2023] Open
Abstract
Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) is a fast growing and highly heterogeneous tumor, often characterized by the presence of glioblastoma stem cells (GSCs). The plasticity of GSCs results in therapy resistance and impairs anti-tumor immune response by influencing immune cells in the tumor microenvironment (TME). Previously, β-catenin was associated with stemness in GBM as well as with immune escape mechanisms. Here, we investigated the effect of β-catenin on attracting monocytes towards GBM cells. In addition, we evaluated whether CCL2 is involved in β-catenin crosstalk between monocytes and tumor cells. Our analysis revealed that shRNA targeting β-catenin in GBMs reduces monocytes attraction and impacts CCL2 secretion. The addition of recombinant CCL2 restores peripheral blood mononuclear cells (PBMC) migration towards medium (TCM) conditioned by shβ-catenin GBM cells. CCL2 knockdown in GBM cells shows similar effects and reduces monocyte migration to a similar extent as β-catenin knockdown. When investigating the effect of CCL2 on β-catenin activity, we found that CCL2 modulates components of the Wnt/β-catenin pathway and alters the clonogenicity of GBM cells. In addition, the pharmacological β-catenin inhibitor MSAB reduces active β-catenin, downregulates the expression of associated genes and alters CCL2 secretion. Taken together, we showed that β-catenin plays an important role in attracting monocytes towards GBM cells in vitro. We hypothesize that the interactions between β-catenin and CCL2 contribute to maintenance of GSCs via modulating immune cell interaction and promoting GBM growth and recurrence.
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41
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He Y, Qu Y, Meng B, Huang W, Tang J, Wang R, Chen Z, Kou X, Shi S. Mesenchymal stem cells empower T cells in the lymph nodes via MCP-1/PD-L1 axis. Cell Death Dis 2022; 13:365. [PMID: 35436982 PMCID: PMC9016066 DOI: 10.1038/s41419-022-04822-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/25/2022] [Accepted: 04/04/2022] [Indexed: 11/18/2022]
Abstract
Mesenchymal stem cells (MSCs) are a type of immunosuppressive stromal cell found in multiple tissues and organs. However, whether MSCs possess immunosupportive characteristics remains unclear. In this study, we showed that the lymph nodes contain immunosupportive MSCs. They produce and secrete a high level of MCP-1 to promote T-cell proliferation and differentiation, in contrast to bone marrow MSCs (BMMSCs), which repress T-cell activation. Unlike BMMSCs, lymph node MSCs (LNMSCs) fail to respond to activated T-cell-induced production of PD-L1 to induce T-cell apoptosis. Mechanistically, MCP-1 activates phospho-Erk to sustain T-cell proliferation and activation while it represses NF-κB/PD-L1 pathway to avoid induction of T-cell apoptosis. Interestingly, inflammatory lymph node-derived LNMSCs abolish their immunosupportive function due to reduction of MCP-1 expression. Finally, we show that systemic infusion of LNMSCs rescues immunosuppression in cytoxan (CTX)-treated mice. This study reveals a previously unrecognized mechanism underlying MSC-based immunoregulation using the MCP-1/PD-L1 axis to energize T cells and suggests a potential to use MSCs to treat immunosuppressive disorders.
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42
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Sasai M, Yamamoto M. Anti-toxoplasma host defense systems and the parasitic counterdefense mechanisms. Parasitol Int 2022; 89:102593. [DOI: 10.1016/j.parint.2022.102593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 04/12/2022] [Accepted: 04/26/2022] [Indexed: 10/18/2022]
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43
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Bose S, Saha P, Chatterjee B, Srivastava AK. Chemokines driven ovarian cancer progression, metastasis and chemoresistance: potential pharmacological targets for cancer therapy. Semin Cancer Biol 2022; 86:568-579. [DOI: 10.1016/j.semcancer.2022.03.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 12/18/2022]
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Pre-infection plasma cytokines and chemokines as predictors of HIV disease progression. Sci Rep 2022; 12:2437. [PMID: 35165387 PMCID: PMC8844050 DOI: 10.1038/s41598-022-06532-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 02/02/2022] [Indexed: 01/13/2023] Open
Abstract
Previous studies have highlighted the role of pre-infection systemic inflammation on HIV acquisition risk, but the extent to which it predicts disease progression outcomes is less studied. Here we examined the relationship between pre-infection plasma cytokine expression and the rate of HIV disease progression in South African women who seroconverted during the CAPRISA 004 tenofovir gel trial. Bio-Plex 200 system was used to measure the expression of 47 cytokines/chemokines in 69 seroconvertors from the CAPRISA 004 trial. Cox proportional hazards regression analyses were used to measure associations between cytokine expression and CD4 decline prior to antiretroviral therapy initiation. Linear regression models were used to assess whether pre-infection cytokine expression were predictors of disease progression outcomes including peak and set-point viral load and CD4:CD8 ratio at less and greater than180 days post infection. Several cytokines were associated with increased peak HIV viral load (including IL-16, SCGFβ, MCP-3, IL-12p40, SCF, IFNα2 and IL-2). The strongest association with peak viral load was observed for SCGFβ, which was also inversely associated with lowest CD4:CD8 ratio < 180 days post infection and faster CD4 decline below 500 cells/µl (adjusted HR 4.537, 95% CI 1.475–13.954; p = 0.008) in multivariable analysis adjusting for age, study site, contraception, baseline HSV-2 status and trial arm allocation. Our results show that pre-infection systemic immune responses could play a role in HIV disease progression, especially in the early stages of infection.
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45
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You R, Jiang H, Xu Q, Yin G. Preintervention MCP-1 serum levels as an early predictive marker of tumor response in patients with hepatocellular carcinoma undergoing transarterial chemoembolization. Transl Cancer Res 2022; 10:966-976. [PMID: 35116424 PMCID: PMC8797576 DOI: 10.21037/tcr-20-2791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 12/04/2020] [Indexed: 12/17/2022]
Abstract
Background Transarterial chemoembolization (TACE) is a widely accepted treatment for unresectable or intermediate-stage hepatocellular carcinoma (HCC). However, response rates to TACE are heterogeneous and it is not fully understood which patients benefit most from TACE therapy in terms of tumor response. To identify the possible predictive roles of the perioperative monocyte chemoattractant protein-1 (MCP-1) levels in patients of HCC treated with TACE. Methods Forty patients of HCC receiving TACE were enrolled in a single center prospective observational study. MCP-1 and miR-210 levels were measured in 40 HCC patients at baseline before TACE and compared with 17 healthy controls by immunoassay and reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Tumor response assessments were taken after TACE treatment 4–6 weeks. Univariate and multivariate analysis were conducted to analyze factors correlated with tumor response in a Logistic regression model. The predictive roles of the involved variables on tumor response in patients with HCC suffering TACE were examined by receiver operating characteristic (ROC) curve analysis. Results The serum MCP-1 and miR-210 levels were significantly elevated in HCC patients compared to healthy subjects. Patients with the low preintervention MCP-1 and miR-210 levels attained a higher probability of achieving an objective response (OR) (88.5% vs.42.9%, P=0.007; 76.9% vs. 35.7%, P=0.010, respectively). Pre-TACE MCP-1 level (<816.63 pg/mL) was an independent risk factor associated with OR after TACE by univariate and multivariate analysis while Pre-TACE miR-210 level (<4.43 relative expression) was just positive by univariate analysis. ROC curve analysis showed that a combined index based on those two factors exhibited optimal predictive power of tumor response among all the involved variables (area under the curve =0.823, 95% CI: 0.681–0.965). Additionally, high pre-TACE serum MCP-1 level was correlated with cirrhosis, vascular invasion and Barcelona Clinic Liver Cancer (BCLC) stage. Elevated pre-TACE serum miR-210 level was associated with and BCLC stage. Conclusions The study demonstrates that the pre-TACE serum MCP-1 level serves as an effective predictor for tumor response. These findings probably help discriminate HCC patients pre-TACE who specially benefit from TACE regarding OR.
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Affiliation(s)
- Ran You
- Department of Interventional Radiology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Jiang
- Department of Interventional Radiology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Qingyu Xu
- Department of Interventional Radiology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Guowen Yin
- Department of Interventional Radiology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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46
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Proma MA, Daria S, Nahar Z, Ashraful Islam SM, Bhuiyan MA, Islam MR. Monocyte chemoattractant protein-1 levels are associated with major depressive disorder. J Basic Clin Physiol Pharmacol 2022; 33:735-741. [PMID: 34983131 DOI: 10.1515/jbcpp-2021-0132] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 12/15/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Major depressive disorder (MDD) is a distressing condition characterized by persistent low mood, loss of interest in daily activities. Researchers consider several biological, psycho-social, and genetic factors are involved in depression. The present study aimed to investigate the serum levels of monocyte chemoattractant protein-1 (MCP-1) in MDD patients to explore its role in depression. METHODS This case-control study recruited 114 MDD patients and 106 healthy controls (HCs) matched by age and gender. A specialized psychiatrist diagnosed the cases and evaluated the controls based on the diagnostic and statistical manual for mental disorders, 5th edition. We quantified serum MCP-1 levels using commercially available enzyme-linked immune sorbent assay kits. Also, we applied the Hamilton depression rating scale (Ham-D) to measure the severity of depression. RESULTS We observed the decreased levels of serum MCP-1 in MDD patients compared to HCs. Also, we obtained a significant negative correlation between serum MCP-1 levels and Ham-D scores. Moreover, female MDD patients with higher Ham-D scores exhibited lower serum MCP-1 levels. The receiver operating characteristic analysis demonstrated the good diagnostic value of MCP-1 with the area under the curve at 0.837. CONCLUSIONS The depression-related alteration of serum MCP-1 may be more complicated than the current assumption and depends on the characteristics of the individual patients. Our study suggests that the serum MCP-1 levels might involve in the pathophysiology and mechanism of MDD. The present findings, along with the diagnostic evaluation, might be used to evaluate depressive patients.
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Affiliation(s)
| | - Sohel Daria
- Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh
| | - Zabun Nahar
- Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh
| | | | | | - Md Rabiul Islam
- Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh
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47
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Kumar R, Bhatia M, Pai K. Role of Chemokines in the Pathogenesis of Visceral Leishmaniasis. Curr Med Chem 2022; 29:5441-5461. [PMID: 35579167 DOI: 10.2174/0929867329666220509171244] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 12/23/2021] [Accepted: 03/02/2022] [Indexed: 11/22/2022]
Abstract
Visceral leishmaniasis (VL; also known as kala-azar), caused by the protozoan parasite Leishmania donovani, is characterized by the inability of the host to generate an effective immune response. The manifestations of the disease depend on the involvement of various immune components such as activation of macrophages, cell mediated immunity, secretion of cytokines and chemokines, etc. Macrophages are the final host cells for Leishmania parasites to multiply, and they are the key to a controlled or aggravated response that leads to clinical symptoms. The two most common macrophage phenotypes are M1 and M2. The pro-inflammatory microenvironment (mainly by IL-1β, IL-6, IL-12, IL-23, and TNF-α cytokines) and tissue injury driven by classically activated macrophages (M1-like) and wound healing driven by alternatively activated macrophages (M2-like) in an anti-inflammatory environment (mainly by IL-10, TGF-β, chemokine ligand (CCL)1, CCL2, CCL17, CCL18, and CCL22). Moreover, on polarized Th cells, chemokine receptors are expressed differently. Typically, CXCR3 and CCR5 are preferentially expressed on polarized Th1 cells, whereas CCR3, CCR4, and CCR8 have been associated with the Th2 phenotype. Further, the ability of the host to produce a cell-mediated immune response capable of regulating and/or eliminating the parasite is critical in the fight against the disease. Here, we review the interactions between parasites and chemokines and chemokine receptors in the pathogenesis of VL.
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Affiliation(s)
- Ramesh Kumar
- Department of Biochemistry, Bundelkhand University, Jhansi (UP), India
| | - Madhav Bhatia
- Department of Pathology and Biomedical Sciences, University of Otago, Christchurch, New Zealand
| | - Kalpana Pai
- Department of Zoology, Savitribai Phule Pune University, Pune, Maharashtra, India
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48
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Heidari S, Kolahdouz-Mohammadi R, Khodaverdi S, Tajik N, Delbandi AA. Expression levels of MCP-1, HGF, and IGF-1 in endometriotic patients compared with non-endometriotic controls. BMC Womens Health 2021; 21:422. [PMID: 34930225 PMCID: PMC8686524 DOI: 10.1186/s12905-021-01560-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/02/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND To study the concentrations of monocyte chemoattractant protein-1 (MCP-1), hepatocyte growth factor (HGF), and insulin-like growth factor-1 (IGF-1) in peritoneal fluid (PF) and serum, and to evaluate their expressions by PF and peripheral blood mononuclear cells (PFMCs and PBMCs, respectively), and ectopic and eutopic endometrial stromal cells of patients with endometriosis (EESCs and EuESCs, respectively) compared with controls. METHODS The concentrations of mentioned cytokines in serum and PF, as well as their expression in PBMCs, PFMCs, EuESCs and EESCs from endometriosis patients and controls were assessed. RESULTS The levels of MCP-1, HGF, and IGF-1 in serum and PF in women with endometriosis were significantly higher than the controls (P < 0.05-P < 0.001). Gene expression of MCP-1 and IGF-1 in the PFMCs, PBMCs and EESCs also showed an increased level compared to controls (P < 0.05-P < 0.01). The protein expression of MCP-1 and IGF-1 by PFMCs was statistically higher in endometriotic women (P < 0.05 and P < 0.01, respectively). The gene and protein expression of HGF in PFMCs and its gene expression by EESCs were significantly higher in endometriotic women compared to controls (P < 0.05-P < 0.01). CONCLUSIONS The higher concentrations of mentioned cytokines in serum and PF and their higher expression by PFMCs and EESCs in endometriosis patients may contribute to the development of endometriosis.
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Affiliation(s)
- Sahel Heidari
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Roya Kolahdouz-Mohammadi
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Sepideh Khodaverdi
- Endometriosis Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Nader Tajik
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Delbandi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran. .,Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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49
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Kiselevskii MV, Vlasenko RY, Stepanyan NG, Shubina IZ, Sitdikova SM, Kirgizov KI, Varfolomeeva SR. Secretome of Mesenchymal Bone Marrow Stem Cells: Is It Immunosuppressive or Proinflammatory? Bull Exp Biol Med 2021; 172:250-253. [PMID: 34855084 PMCID: PMC8636784 DOI: 10.1007/s10517-021-05371-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Indexed: 11/30/2022]
Abstract
Mesenchymal stem cells (MSC) are characterized by tolerogenic potential and therefore, are used in the treatment of autoimmune diseases such as graft-versus-host disease (GVHD) reactions after allogeneic hematopoietic cell transplantation to improve the transplant functions, as well as for the therapy and prevention of cytokine storm in COVID-19 patients and some other conditions. However, MSC can exhibit proinflammatory activity, which causes risks for their clinical use. We studied the cytokine profile of bone marrow MSC culture and demonstrate intensive production of IL-6, IL-8, and chemokine MCP-1, which participate in the pathogenesis of cytokine storm and GVHD. At the same time, no anti-inflammatory IL-4 and IL-10 were detected. To reduce the risks of MSC application in the GVHD therapeutic protocols, further studies of the conditions promoting generation of MSC with tolerogenic potential and approved clinical standards of MSC use are required.
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Affiliation(s)
- M V Kiselevskii
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia.
| | - R Ya Vlasenko
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - N G Stepanyan
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - I Zh Shubina
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - S M Sitdikova
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - K I Kirgizov
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - S R Varfolomeeva
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
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50
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Teng F, Tang W, Wuniqiemu T, Qin J, Zhou Y, Huang X, Wang S, Zhu X, Tang Z, Yi L, Wei Y, Dong J. N 6-Methyladenosine Methylomic Landscape of Lung Tissues in Murine Acute Allergic Asthma. Front Immunol 2021; 12:740571. [PMID: 34737744 PMCID: PMC8560743 DOI: 10.3389/fimmu.2021.740571] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/28/2021] [Indexed: 12/13/2022] Open
Abstract
Allergic asthma is well known as a common respiratory disorder comprising an allergic inflammatory nature and excessive immune characteristic. N 6-methyladenosine (m6A) methylation is an RNA epigenetic modification that post-transcriptionally regulates gene expression and function by affecting the RNA fate. Currently, m6A methylation is gaining attention as a mechanism of immunoregulation. However, whether m6A methylation engages the pathological process of asthma remains uncertain. Here, we present the m6A methylomic landscape in the lung tissues of ovalbumin-induced acute asthma mice using MeRIP-seq and RNA-seq. We identified 353 hypermethylated m6A peaks within 329 messenger RNAs (mRNAs) and 150 hypomethylated m6A peaks within 143 mRNAs in the lung tissues of asthmatic mice. These differentially methylated mRNAs were found to be involved in several immune function-relevant signaling pathways. In addition, we predicted 25 RNA-binding proteins that recognize the differentially methylated peak sites by exploring public databases, and the roles of these proteins are mostly related to mRNA biogenesis and metabolism. To further investigate the expression levels of the differentially methylated genes, we performed combined analysis of the m6A methylome and transcriptome data and identified 127 hypermethylated mRNAs (107 high and 20 low expression) and 43 hypomethylated mRNAs with differential expressions (9 high and 34 low expression). Of these, there are a list of mRNAs involved in immune function and regulation. The present results highlight the essential role of m6A methylation in the pathogenesis of asthma.
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Affiliation(s)
- Fangzhou Teng
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Weifeng Tang
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Tulake Wuniqiemu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Jingjing Qin
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Yaolong Zhou
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Xi Huang
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Shiyuan Wang
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Xueyi Zhu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Zhao Tang
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - La Yi
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Ying Wei
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Jingcheng Dong
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Institutes of Integrative Medicine, Fudan University, Shanghai, China
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