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Kaden T, Alonso‐Román R, Stallhofer J, Gresnigt MS, Hube B, Mosig AS. Leveraging Organ-on-Chip Models to Investigate Host-Microbiota Dynamics and Targeted Therapies for Inflammatory Bowel Disease. Adv Healthc Mater 2025; 14:e2402756. [PMID: 39491534 PMCID: PMC12004439 DOI: 10.1002/adhm.202402756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/29/2024] [Indexed: 11/05/2024]
Abstract
Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.
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Affiliation(s)
- Tim Kaden
- Dynamic42 GmbH07745JenaGermany
- Institute of Biochemistry IICenter for Sepsis Control and CareJena University Hospital07747JenaGermany
| | - Raquel Alonso‐Román
- Department of Microbial Pathogenicity MechanismsLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Junior Research Group Adaptive Pathogenicity StrategiesLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
| | | | - Mark S. Gresnigt
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Junior Research Group Adaptive Pathogenicity StrategiesLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
| | - Bernhard Hube
- Department of Microbial Pathogenicity MechanismsLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Institute of MicrobiologyFaculty of Biological SciencesFriedrich Schiller University07743JenaGermany
| | - Alexander S. Mosig
- Institute of Biochemistry IICenter for Sepsis Control and CareJena University Hospital07747JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
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Zhu C, Boucheron N, Al-Rubaye O, Chung BK, Thorbjørnsen LW, Köcher T, Schuster M, Claudel T, Halilbasic E, Kunczer V, Muscate F, Cavanagh LL, Waltenberger D, Lercher A, Ohradanova-Repic A, Schatzlmaier P, Stojakovic T, Scharnagl H, Bergthaler A, Stockinger H, Huber S, Bock C, Kenner L, Karlsen TH, Ellmeier W, Trauner M. 24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting T H17 pathogenicity and transdifferentiation. Gut 2025:gutjnl-2024-333297. [PMID: 40032499 DOI: 10.1136/gutjnl-2024-333297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 01/28/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND 24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC). OBJECTIVE Since PSC strongly associates with T helper-type-like 17 (TH17)-mediated intestinal inflammation, we explored NorUDCA's immunomodulatory potential on TH17 cells. DESIGN NorUDCA's impact on TH17 differentiation was assessed using a CD4+TNaive adoptive transfer mouse model, and on intraepithelial TH17 pathogenicity and transdifferentiation using an αCD3 stimulation model combined with interleukin-17A-fate-mapping. Mechanistic studies used molecular and multiomics approaches, flow cytometry and metabolic assays with pathogenic (p) TH17. Pathogenicity of pTH17 exposed to NorUDCA in vitro was evaluated following adoptive transfer in intestinal tissues or the central nervous system (CNS). Key findings were validated in an αCD3-stimulated humanised NSG mouse model reconstituted with peripheral blood mononuclear cells from patients with PSC. RESULTS NorUDCA suppressed TH17 effector function and enriched regulatory T cell (Treg) abundance upon CD4+TNaive cell transfer. NorUDCA mitigated intraepithelial TH17 pathogenicity and decreased the generation of proinflammatory 'TH1-like-TH17' cells, and enhanced TH17 transdifferentiation into Treg and Tr1 (regulatory type 1) cells in the αCD3-model. In vivo ablation revealed that Treg induction is crucial for NorUDCA's anti-inflammatory effect on TH17 pathogenicity. Mechanistically, NorUDCA restrained pTH17 effector function and simultaneously promoted functional Treg formation in vitro, by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pTH17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA's impact on TH17 inflammation was corroborated in the humanised NSG mouse model. CONCLUSION NorUDCA restricts TH17 inflammation in multiple mouse models, potentiating future clinical applications for treating TH17-mediated intestinal diseases and beyond.
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Affiliation(s)
- Ci Zhu
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Nicole Boucheron
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Osamah Al-Rubaye
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Brian K Chung
- Department of Transplantation Medicine, Clinic of Surgery and Specialized Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Liv Wenche Thorbjørnsen
- Department of Transplantation Medicine, Clinic of Surgery and Specialized Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Thomas Köcher
- Vienna BioCenter Core Facilities, Metabolomics, Vienna BioCenter, Vienna, Austria
| | - Michael Schuster
- Biomedical Sequencing Facility, Cemm, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Victoria Kunczer
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Fanziska Muscate
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Lois L Cavanagh
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Darina Waltenberger
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Alexander Lercher
- Cemm, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Anna Ohradanova-Repic
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Philipp Schatzlmaier
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Andreas Bergthaler
- Cemm, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Hannes Stockinger
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Bock
- Biomedical Sequencing Facility, Cemm, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Lukas Kenner
- Division of Experimental and Translational Pathology, Department of Pathology, Medical University of Vienna, Vienna, Austria
- Unit of Laboratory Animal Pathology, Department for Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Tom H Karlsen
- Department of Transplantation Medicine, Clinic of Surgery and Specialized Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Wilfried Ellmeier
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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Povoleri GAM, Ridley ML, Marrow RJ, Lalnunhlimi S, Ryan SE, Kelly A, Lavender P, Taams LS. Identification of a transcription factor network regulating anti-TNF mediated IL10 expression in human CD4+ T cells. DISCOVERY IMMUNOLOGY 2024; 3:kyae013. [PMID: 39290825 PMCID: PMC11407445 DOI: 10.1093/discim/kyae013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/27/2024] [Accepted: 07/25/2024] [Indexed: 09/19/2024]
Abstract
CD4+ T cells are key players in immune-mediated inflammatory diseases (IMIDs) through the production of inflammatory mediators including tumour necrosis factor (TNF). Anti-TNF therapy has revolutionized the treatment of several IMIDs and we previously demonstrated that in vitro treatment of human CD4+ T cells with anti-TNF promotes anti-inflammatory IL-10 expression in multiple subpopulations of CD4+ T cells. Here we investigated the transcriptional mechanisms underlying the IL-10 induction by TNF-blockade in CD4+ T cells, isolated from PBMCs of healthy volunteers, stimulated in vitro for 3 days with anti-CD3/CD28 mAb in the absence or presence of anti-TNF. After culture, CD45RA+ cells were depleted before performing gene expression profiling and chromatin accessibility analysis. Gene expression analysis of CD45RA-CD4+ T cells showed a distinct anti-TNF specific gene signature of 183 genes (q-value < 0.05). Pathway enrichment analysis of differentially expressed genes revealed multiple pathways related to cytokine signalling and regulation of cytokine production; in particular, IL10 was the most upregulated gene by anti-TNF, while the proinflammatory cytokines and chemokines IFNG, IL9, IL22, and CXCL10 were significantly downregulated (q-value < 0.05). Transcription factor motif analysis at the differentially open chromatin regions, after anti-TNF treatment, revealed 58 transcription factor motifs enriched at the IL10 locus. We identified seven transcription factor candidates for the anti-TNF mediated regulation of IL-10, which were either differentially expressed or whose locus was differentially accessible upon anti-TNF treatment. Correlation analysis between the expression of these transcription factors and IL10 suggests a role for MAF, PRDM1, and/or EOMES in regulating IL10 expression in CD4+ T cells upon anti-TNF treatment.
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Affiliation(s)
- Giovanni A M Povoleri
- Centre for Inflammation Biology and Cancer Immunology (CIBCI), Department of Inflammation Biology, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Michael L Ridley
- Centre for Inflammation Biology and Cancer Immunology (CIBCI), Department of Inflammation Biology, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Rebecca J Marrow
- Centre for Inflammation Biology and Cancer Immunology (CIBCI), Department of Inflammation Biology, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Sylvine Lalnunhlimi
- Centre for Inflammation Biology and Cancer Immunology (CIBCI), Department of Inflammation Biology, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Sarah E Ryan
- Centre for Inflammation Biology and Cancer Immunology (CIBCI), Department of Inflammation Biology, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Audrey Kelly
- King's Centre for Lung Health, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Paul Lavender
- King's Centre for Lung Health, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Leonie S Taams
- Centre for Inflammation Biology and Cancer Immunology (CIBCI), Department of Inflammation Biology, School of Immunology & Microbial Sciences, King's College London, London, UK
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Niu Q, Wang M, Liu XS. The evolving landscape of IL-10, IL-22 and IL-26 in pleurisy especially in tuberculous pleurisy. Respir Res 2024; 25:275. [PMID: 39003443 PMCID: PMC11245850 DOI: 10.1186/s12931-024-02896-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: 04/22/2024] [Accepted: 06/29/2024] [Indexed: 07/15/2024] Open
Abstract
Pleurisy can be categorized as primary or secondary, arising from immunological, tumorous, or microbial conditions. It often results in lung structure damage and the development of various respiratory issues. Among the different types, tuberculous pleurisy has emerged as a prominent focus for both clinical and scientific investigations. The IL-10 family, known for its anti-inflammatory properties in the human immune system, is increasingly being studied for its involvement in the pathogenesis of pleurisy. This review aims to present a detailed overview of the intricate role of IL-10 family members (specifically IL-10, IL-22, and IL-26) in human and animal pleuritic diseases or relevant animal models. These insights could serve as valuable guidance and references for further studies on pleurisy and potential therapeutic strategies.
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Affiliation(s)
- Qian Niu
- Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Meng Wang
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Department of Pathology, Baoji Gaoxin Hospital, Baoji, 721000, China
| | - Xian-Sheng Liu
- Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Wang S, Yang N, Zhang H. Metabolic dysregulation of lymphocytes in autoimmune diseases. Trends Endocrinol Metab 2024; 35:624-637. [PMID: 38355391 DOI: 10.1016/j.tem.2024.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 01/13/2024] [Accepted: 01/17/2024] [Indexed: 02/16/2024]
Abstract
Lymphocytes are crucial for protective immunity against infection and cancers; however, immune dysregulation can lead to autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Metabolic adaptation controls lymphocyte fate; thus, metabolic reprogramming can contribute to the pathogenesis of autoimmune diseases. Here, we summarize recent advances on how metabolic reprogramming determines the autoreactive and proinflammatory nature of lymphocytes in SLE and RA, unraveling molecular mechanisms and providing therapeutic targets for human autoimmune diseases.
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Affiliation(s)
- Shuyi Wang
- Department of Rheumatology and Clinical Immunology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Niansheng Yang
- Department of Rheumatology and Clinical Immunology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Hui Zhang
- Department of Rheumatology and Clinical Immunology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute of Precision Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
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He BX, Fang SB, Xie YC, Lou DX, Wu ZC, Li CG, Liu XQ, Zhou ZR, Huang LX, Tian T, Chen DH, Fu QL. Small extracellular vesicles derived from human mesenchymal stem cells prevent Th17-dominant neutrophilic airway inflammation via immunoregulation on Th17 cells. Int Immunopharmacol 2024; 133:112126. [PMID: 38669946 DOI: 10.1016/j.intimp.2024.112126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/18/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024]
Abstract
Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation is critical in the pathogenesis of steroid-resistant airway inflammation such as severe asthma. Small extracellular vesicles (sEV) derived from human mesenchymal stem cells (MSCs) display extensive therapeutic effects and advantages in many diseases. However, the role of MSC-sEV in Th17-dominant neutrophilic airway inflammation and the related mechanisms are still poorly studied. Here we found that MSC-sEV significantly alleviated the infiltration of inflammatory cells in peribronchial interstitial tissues and reduced levels of inflammatory cells, especially neutrophils, in bronchoalveolar lavage fluids (BALF) of mice with neutrophilic airway inflammation. Consistently, MSC-sEV significantly decreased levels of IL-17A in BALF and Th17 in lung tissues. Furthermore, we found that labelled MSC-sEV were taken up by human CD4+ T cells most obviously at 12 h after incubation, and distributed mostly in mouse lungs. More importantly, potential signaling pathways involved in the MSC-sEV mediated inhibition of Th17 polarization were found using RNA sequencing. Using Western blot, JAK2-STAT3 pathway was identified as an important role in the inhibition of Th17 polarization by MSC-sEV. We found that proteins in MSC-sEV were mostly involved in the therapeutic effects of MSC-sEV. In total, our study suggested that MSC-sEV could be a potential therapeutic strategy for the treatment of neutrophilic airway inflammation.
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Affiliation(s)
- Bi-Xin He
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shu-Bing Fang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ying-Chun Xie
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dong-Xiao Lou
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Zi-Cong Wu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Chan-Gu Li
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Xiao-Qing Liu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Rou Zhou
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Long-Xin Huang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tian Tian
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - De-Hua Chen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Division of Allergy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
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Hammitzsch A, Ossadnik A, Bachmann Q, Merwald-Fraenk H, Lorenz G, Witt M, Wiesent F, Mühlhofer H, Simone D, Bowness P, Heemann U, Arbogast M, Moog P, Schmaderer C. Increased interleukin-26 in the peripheral joints of patients with axial spondyloarthritis and psoriatic arthritis, co-localizing with CD68-positive synoviocytes. Front Immunol 2024; 15:1355824. [PMID: 38799447 PMCID: PMC11127564 DOI: 10.3389/fimmu.2024.1355824] [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: 12/14/2023] [Accepted: 04/01/2024] [Indexed: 05/29/2024] Open
Abstract
Objectives IL26 levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. IL26 can be produced by Th17 cells and locally within joints by tissue-resident cells. IL26 induces osteoblast mineralization in vitro. As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of IL26 in spondyloarthritis. Methods Serum, peripheral blood mononuclear cells (n = 15-35) and synovial tissue (n = 3-9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, n = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR. Results Synovial tissue of axSpA patients shows significantly more IL26-positive cells than that of HCs (p < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of IL26 with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. IL26 is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs (p < 0.001 and p < 0.01). However, peripheral blood CD4+ T cells from axSpA and PsA patients show higher positivity for IL26 in the PrimeFlow assay compared with HCs. CD4+ memory T cells from axSpA patients produce more IL26 under Th17-favoring conditions (IL-1β and IL-23) than cells from PsA and RA patients or HCs. Conclusion IL26 production is increased in the synovial tissue of SpA and can be localized to CD68+ macrophage-like synoviocytes, whereas circulating IL26+ Th17 cells are only modestly enriched. Considering the osteoproliferative properties of IL26, this offers new therapeutic options independent of Th17 pathways.
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Affiliation(s)
- Ariane Hammitzsch
- Department of Nephrology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Andreas Ossadnik
- Department of Nephrology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Quirin Bachmann
- Department of Nephrology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Helga Merwald-Fraenk
- Amedes Holding AG, Ambulatory Healthcare Center (MVZ) Endokrinologikum München, Munich, Germany
| | - Georg Lorenz
- Department of Nephrology and Rheumatology, Klinik Augustinum München, Munich, Germany
| | | | - Franziska Wiesent
- Amedes Holding AG, Ambulatory Healthcare Center (MVZ) Endokrinologikum München, Munich, Germany
| | - Heinrich Mühlhofer
- Clinic and Policlinic of Orthopaedics and Sports’ Orthopaedics, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Davide Simone
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Paul Bowness
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Uwe Heemann
- Department of Nephrology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Martin Arbogast
- Department of Rheumatic Orthopedics and Hand Surgery, Klinik Oberammergau, Waldburg-Zeil Kliniken GmbH und Co KG, Oberammergau, Germany
| | - Philipp Moog
- Department of Nephrology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Christoph Schmaderer
- Department of Nephrology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
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8
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Sieminska I, Pieniawska M, Grzywa TM. The Immunology of Psoriasis-Current Concepts in Pathogenesis. Clin Rev Allergy Immunol 2024; 66:164-191. [PMID: 38642273 PMCID: PMC11193704 DOI: 10.1007/s12016-024-08991-7] [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] [Accepted: 04/01/2024] [Indexed: 04/22/2024]
Abstract
Psoriasis is one of the most common inflammatory skin diseases with a chronic, relapsing-remitting course. The last decades of intense research uncovered a pathological network of interactions between immune cells and other types of cells in the pathogenesis of psoriasis. Emerging evidence indicates that dendritic cells, TH17 cells, and keratinocytes constitute a pathogenic triad in psoriasis. Dendritic cells produce TNF-α and IL-23 to promote T cell differentiation toward TH17 cells that produce key psoriatic cytokines IL-17, IFN-γ, and IL-22. Their activity results in skin inflammation and activation and hyperproliferation of keratinocytes. In addition, other cells and signaling pathways are implicated in the pathogenesis of psoriasis, including TH9 cells, TH22 cells, CD8+ cytotoxic cells, neutrophils, γδ T cells, and cytokines and chemokines secreted by them. New insights from high-throughput analysis of lesional skin identified novel signaling pathways and cell populations involved in the pathogenesis. These studies not only expanded our knowledge about the mechanisms of immune response and the pathogenesis of psoriasis but also resulted in a revolution in the clinical management of patients with psoriasis. Thus, understanding the mechanisms of immune response in psoriatic inflammation is crucial for further studies, the development of novel therapeutic strategies, and the clinical management of psoriasis patients. The aim of the review was to comprehensively present the dysregulation of immune response in psoriasis with an emphasis on recent findings. Here, we described the role of immune cells, including T cells, B cells, dendritic cells, neutrophils, monocytes, mast cells, and innate lymphoid cells (ILCs), as well as non-immune cells, including keratinocytes, fibroblasts, endothelial cells, and platelets in the initiation, development, and progression of psoriasis.
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Affiliation(s)
- Izabela Sieminska
- University Centre of Veterinary Medicine, University of Agriculture in Krakow, Krakow, Poland
| | - Monika Pieniawska
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
| | - Tomasz M Grzywa
- Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland.
- The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, USA.
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Lobão B, Lourenço D, Giga A, Mendes-Bastos P. From PsO to PsA: the role of T RM and Tregs in psoriatic disease, a systematic review of the literature. Front Med (Lausanne) 2024; 11:1346757. [PMID: 38405187 PMCID: PMC10884248 DOI: 10.3389/fmed.2024.1346757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 01/25/2024] [Indexed: 02/27/2024] Open
Abstract
Introduction Psoriasis (PsO) is a chronic skin condition driven by immune mediators like TNFα, INFγ, IL-17, and IL-23. Psoriatic arthritis (PsA) can develop in PsO patients. Although psoriatic lesions may apparently resolve with therapy, subclinical cutaneous inflammation may persist. The role of tissue-resident memory T-cells (TRM), and regulatory T cells (Tregs) that also contribute to chronic inflammation are being explored in this context. This systematic review explores TRM and Tregs in psoriatic disease (PsD) and its progression. Methods A systematic review, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was performed using Pubmed® and Web of Science™ databases on June 3rd 2023, using patient/population, intervention, comparison, and outcomes (PICO) criteria limited to the English language. Results A total of 62 reports were identified and included. In PsO, chronic inflammation is driven by cytokines including IL-17 and IL-23, and cellular mediators such as CD8+ and CD4+ T cells. TRM contributes to local inflammation, while Tregs may be dysfunctional in psoriatic skin lesions. Secukinumab and guselkumab, which target IL-17A and the IL-23p19 subunit, respectively, have different effects on CD8+ TRM and Tregs during PsO treatment. Inhibition of IL-23 may provide better long-term results due to its impact on the Treg to CD8+ TRM ratio. IL-23 may contribute to inflammation persisting even after treatment. In PsA, subclinical enthesitis is perceived as an early occurence, and Th17 cells are involved in this pathogenic process. Recent EULAR guidelines highlight the importance of early diagnosis and treatment to intercept PsA. In PsA, CD8+ TRM cells are present in synovial fluid and Tregs are reduced in peripheral blood. The progression from PsO to PsA is marked by a shift in immune profiles, with specific T-cells subsets playing key roles in perpetuating inflammation. Early intervention targeting TRM cells may hold promising, but clinical studies are limited. Ongoing studies such as IVEPSA and PAMPA aim to improve our knowledge regarding PsA interception in high-risk PsO patients, emphasizing the need for further research in this area. Conclusion Early intervention is crucial for PsO patients at high risk of PsA; T cells, particularly type 17 helper T cells, and CD8+ cells are key in the progression from PsO-to-PsA. Early targeting of TRM in PsD shows promise but more research is needed.
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Affiliation(s)
- Bárbara Lobão
- Instituto Português de Reumatologia, Lisboa, Portugal
- Centro Hospitalar de Setúbal, Setúbal, Portugal
| | | | - Ana Giga
- Janssen Portugal, Oeiras, Portugal
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10
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Blinova VG, Gladilina YA, Abramova AA, Eliseeva DD, Vtorushina VV, Shishparenok AN, Zhdanov DD. Modulation of Suppressive Activity and Proliferation of Human Regulatory T Cells by Splice-Switching Oligonucleotides Targeting FoxP3 Pre-mRNA. Cells 2023; 13:77. [PMID: 38201281 PMCID: PMC10777989 DOI: 10.3390/cells13010077] [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: 11/09/2023] [Revised: 12/05/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
The maturation, development, and function of regulatory T cells (Tregs) are under the control of the crucial transcription factor Forkhead Box Protein 3 (FoxP3). Through alternative splicing, the human FoxP3 gene produces four different splice variants: a full-length variant (FL) and truncated variants with deletions of each of exons 2 (∆2 variant) or 7 (∆7 variant) or a deletion of both exons (∆2∆7 variant). Their involvement in the biology of Tregs as well as their association with autoimmune diseases remains to be clarified. The aim of this work was to induce a single FoxP3 splice variant in human Tregs by splice switching oligonucleotides and to monitor their phenotype and proliferative and suppressive activity. We demonstrated that Tregs from peripheral blood from patients with multiple sclerosis preferentially expressed truncated splice variants, while the FL variant was the major variant in healthy donors. Tregs with induced expression of truncated FoxP3 splice variants demonstrated lower suppressive activity than those expressing FL variants. Reduced suppression was associated with the decreased expression of Treg-associated suppressive surface molecules and the production of cytokines. The deletion of exons 2 and/or 7 also reduced the cell proliferation rate. The results of this study show an association between FoxP3 splice variants and Treg function and proliferation. The modulation of Treg suppressive activity by the induction of the FoxP3 FL variant can become a promising strategy for regenerative immunotherapy.
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Affiliation(s)
- Varvara G. Blinova
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia; (V.G.B.); (Y.A.G.); (A.A.A.); (A.N.S.)
| | - Yulia A. Gladilina
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia; (V.G.B.); (Y.A.G.); (A.A.A.); (A.N.S.)
| | - Anna A. Abramova
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia; (V.G.B.); (Y.A.G.); (A.A.A.); (A.N.S.)
- Research Center of Neurology, Volokolamskoe Shosse, 80, 125367 Moscow, Russia;
| | - Daria D. Eliseeva
- Research Center of Neurology, Volokolamskoe Shosse, 80, 125367 Moscow, Russia;
| | - Valentina V. Vtorushina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of the Russian Federation, Laboratory of Clinical Immunology, Academician Oparin st. 4, 117997 Moscow, Russia;
| | - Anastasia N. Shishparenok
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia; (V.G.B.); (Y.A.G.); (A.A.A.); (A.N.S.)
| | - Dmitry D. Zhdanov
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia; (V.G.B.); (Y.A.G.); (A.A.A.); (A.N.S.)
- Department of Biochemistry, People’s Friendship University of Russia Named after Patrice Lumumba (RUDN University), Miklukho-Maklaya st. 6, 117198 Moscow, Russia
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11
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Tout I, Noack M, Miossec P. Differential effects of interleukin-17A and 17F on cell interactions between immune cells and stromal cells from synovium or skin. Sci Rep 2023; 13:19223. [PMID: 37932356 PMCID: PMC10628108 DOI: 10.1038/s41598-023-45653-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 10/22/2023] [Indexed: 11/08/2023] Open
Abstract
We compared the contribution of IL-17A and IL-17F in co-culture systems mimicking cell interactions as found in inflamed synovium and skin. Synoviocytes or skin fibroblasts were co-cultured with activated PBMC, with IL-17A, IL-17 A/F, IL-17F, IL-23, anti-IL-17A, anti-IL-17A/F or anti-IL-17F antibodies. IL-17A, IL-17F, IL-6 and IL-10 production was measured at 48 h. mRNA expression of receptor subunits for IL-23, IL-12 and IL-17 was assessed at 24 h. Both cell activation and interactions were needed for a high IL-17A secretion while IL-17F was stimulated by PHA activation alone and further increased in co-cultures. IL-17F levels were higher than IL-17A in both co-cultures (p < 0.05). IL-17F addition decreased IL-17A secretion (p < 0.05) but IL-17A addition had no effect on IL-17F secretion. Interestingly, IL-17A and IL-17F upregulated IL-17RA and IL-17RC mRNA expression in PBMC/skin fibroblast co-cultures (p < 0.05) while only IL-17F exerted this effect in synoviocytes (p < 0.05). Monocyte exclusion in both co-cultures increased IL-17A and IL-17F (twofold, p < 0.05) while decreasing IL-10 and IL-6 secretion (twofold, p < 0.05). IL-17A and F had differential effects on their receptor expression with a higher sensitivity for skin fibroblasts highlighting the differential contribution of IL-17A and F in joint vs. skin diseases.
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Affiliation(s)
- Issam Tout
- Immunogenomics and Inflammation Research Unit, Hospices Civils de Lyon, Edouard Herriot Hospital, 5 Place d'Arsonval, 69003, Lyon, France
| | - Mélissa Noack
- Immunogenomics and Inflammation Research Unit, Hospices Civils de Lyon, Edouard Herriot Hospital, 5 Place d'Arsonval, 69003, Lyon, France
| | - Pierre Miossec
- Immunogenomics and Inflammation Research Unit, Hospices Civils de Lyon, Edouard Herriot Hospital, 5 Place d'Arsonval, 69003, Lyon, France.
- Department of Clinical Immunology and Rheumatology, Edouard Herriot Hospital, 5 Place d'Arsonval, 69437, Lyon, France.
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12
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Morizane S, Mukai T, Sunagawa K, Tachibana K, Kawakami Y, Ouchida M. "Input/output cytokines" in epidermal keratinocytes and the involvement in inflammatory skin diseases. Front Immunol 2023; 14:1239598. [PMID: 37881433 PMCID: PMC10597658 DOI: 10.3389/fimmu.2023.1239598] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 09/20/2023] [Indexed: 10/27/2023] Open
Abstract
Considering the role of epidermal keratinocytes, they occupy more than 90% of the epidermis, form a physical barrier, and also function as innate immune barrier. For example, epidermal keratinocytes are capable of recognizing various cytokines and pathogen-associated molecular pattern, and producing a wide variety of inflammatory cytokines, chemokines, and antimicrobial peptides. Previous basic studies have shown that the immune response of epidermal keratinocytes has a significant impact on inflammatory skin diseases. The purpose of this review is to provide foundation of knowledge on the cytokines which are recognized or produced by epidermal keratinocytes. Since a number of biologics for skin diseases have appeared, it is necessary to fully understand the relationship between epidermal keratinocytes and the cytokines. In this review, the cytokines recognized by epidermal keratinocytes are specifically introduced as "input cytokines", and the produced cytokines as "output cytokines". Furthermore, we also refer to the existence of biologics against those input and output cytokines, and the target skin diseases. These use results demonstrate how important targeted cytokines are in real skin diseases, and enhance our understanding of the cytokines.
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Affiliation(s)
- Shin Morizane
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tomoyuki Mukai
- Department of Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Japan
| | - Ko Sunagawa
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kota Tachibana
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshio Kawakami
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Mamoru Ouchida
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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13
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Sommer AJ, Okonkwo J, Monteiro J, Bind MAC. A permutation-based approach using a rank-based statistic to identify sex differences in epigenetics. Sci Rep 2023; 13:14838. [PMID: 37684282 PMCID: PMC10491832 DOI: 10.1038/s41598-023-41360-6] [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: 10/17/2022] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Epigenetic sex differences and their resulting implications for human health have been studied for about a decade. The objective of this paper is to use permutation-based inference and a new ranked-based test statistic to identify sex-based epigenetic differences in the human DNA methylome. In particular, we examine whether we could identify separations between the female and male distributions of DNA methylation across hundred of thousands CpG sites in two independent cohorts, the Swedish Adoption Twin study and the Lamarck study. Based on Fisherian p-values, we set a threshold for methylation differences "worth further scrutiny". At this threshold, we were able to confirm previously-found CpG sites that stratify with respect to sex. These CpG sites with sex differences in DNA methylation should be further investigated for their possible contribution to various physiological and pathological functions in the human body. We followed-up our statistical analyses with a literature review in order to inform the proposed disease implications for the loci we uncovered.
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Affiliation(s)
- Alice J Sommer
- Institute for Medical Information Processing, Biometry, and Epidemiology, Faculty of Medicine, Ludwig-Maximilians-University München, Munich, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Jude Okonkwo
- Columbia Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Jonathan Monteiro
- Department of Biostatistics, Massachusetts General Hospital, Boston, MA, USA
| | - Marie-Abèle C Bind
- Department of Biostatistics, Massachusetts General Hospital, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
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14
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Qu Y, Fu Y, Liu Y, Liu C, Xu B, Zhang Q, Jiang P. The role of TRPV1 in RA pathogenesis: worthy of attention. Front Immunol 2023; 14:1232013. [PMID: 37744324 PMCID: PMC10514908 DOI: 10.3389/fimmu.2023.1232013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/28/2023] [Indexed: 09/26/2023] Open
Abstract
Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a Ca2+permeable, non-selective cation channel that is found primarily in sensory nerve fibres. Previous studies focused on pain transmission. However, recent studies have found that the TRPV1 channel, in addition to being associated with pain, also plays a role in immune regulation and their dysregulation frequently affects the development of rheumatoid arthritis (RA). A thorough understanding of the mechanism will facilitate the design of new TRPV1-targeted drugs and improve the clinical efficacy of RA. Here, we provide an updated and comprehensive overview of how the TRPV1 channel intrinsically regulates neuronal and immune cells, and how alterations in the TRPV1 channel in synoviocytes or chondrocytes extrinsically affect angiogenesis and bone destruction. Rapid progress has been made in research targeting TRPV1 for the treatment of inflammatory arthritis, but there is still much-uncharted territory regarding the therapeutic role of RA. We present a strategy for targeting the TRPV1 channel in RA therapy, summarising the difficulties and promising advances in current research, with the aim of better understanding the role of the TRPV1 channel in RA pathology, which could accelerate the development of TRPV1-targeted modulators for the design and development of more effective RA therapies.
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Affiliation(s)
- Yuan Qu
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yang Fu
- Institute of Chinese Orthopedics and Traumatology, Shandong Wendeng Osteopathic Hospital, Weihai, China
| | - Yuan Liu
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chuanguo Liu
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Bing Xu
- Department of Rheumatology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qian Zhang
- Science and Technology Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ping Jiang
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
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15
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Wang J, Zhao X, Wan YY. Intricacies of TGF-β signaling in Treg and Th17 cell biology. Cell Mol Immunol 2023; 20:1002-1022. [PMID: 37217798 PMCID: PMC10468540 DOI: 10.1038/s41423-023-01036-7] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/27/2023] [Indexed: 05/24/2023] Open
Abstract
Balanced immunity is pivotal for health and homeostasis. CD4+ helper T (Th) cells are central to the balance between immune tolerance and immune rejection. Th cells adopt distinct functions to maintain tolerance and clear pathogens. Dysregulation of Th cell function often leads to maladies, including autoimmunity, inflammatory disease, cancer, and infection. Regulatory T (Treg) and Th17 cells are critical Th cell types involved in immune tolerance, homeostasis, pathogenicity, and pathogen clearance. It is therefore critical to understand how Treg and Th17 cells are regulated in health and disease. Cytokines are instrumental in directing Treg and Th17 cell function. The evolutionarily conserved TGF-β (transforming growth factor-β) cytokine superfamily is of particular interest because it is central to the biology of both Treg cells that are predominantly immunosuppressive and Th17 cells that can be proinflammatory, pathogenic, and immune regulatory. How TGF-β superfamily members and their intricate signaling pathways regulate Treg and Th17 cell function is a question that has been intensely investigated for two decades. Here, we introduce the fundamental biology of TGF-β superfamily signaling, Treg cells, and Th17 cells and discuss in detail how the TGF-β superfamily contributes to Treg and Th17 cell biology through complex yet ordered and cooperative signaling networks.
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Affiliation(s)
- Junying Wang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Xingqi Zhao
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yisong Y Wan
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
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16
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Feilstrecker Balani G, dos Santos Cortez M, Picasky da Silveira Freitas JE, Freire de Melo F, Zarpelon-Schutz AC, Teixeira KN. Immune response modulation in inflammatory bowel diseases by Helicobacter pylori infection. World J Gastroenterol 2023; 29:4604-4615. [PMID: 37662864 PMCID: PMC10472898 DOI: 10.3748/wjg.v29.i30.4604] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/01/2023] [Accepted: 07/24/2023] [Indexed: 08/10/2023] Open
Abstract
Many studies point to an association between Helicobacter pylori (H. pylori) infection and inflammatory bowel diseases (IBD). Although controversial, this association indicates that the presence of the bacterium somehow affects the course of IBD. It appears that H. pylori infection influences IBD through changes in the diversity of the gut microbiota, and hence in local chemical characteristics, and alteration in the pattern of gut immune response. The gut immune response appears to be modulated by H. pylori infection towards a less aggressive inflammatory response and the establishment of a targeted response to tissue repair. Therefore, a T helper 2 (Th2)/macrophage M2 response is stimulated, while the Th1/macrophage M1 response is suppressed. The immunomodulation appears to be associated with intrinsic factors of the bacteria, such as virulence factors - such oncogenic protein cytotoxin-associated antigen A, proteins such H. pylori neutrophil-activating protein, but also with microenvironmental changes that favor permanence of H. pylori in the stomach. These changes include the increase of gastric mucosal pH by urease activity, and suppression of the stomach immune response promoted by evasion mechanisms of the bacterium. Furthermore, there is a causal relationship between H. pylori infection and components of the innate immunity such as the NLR family pyrin domain containing 3 inflammasome that directs IBD toward a better prognosis.
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Affiliation(s)
| | | | | | - Fabrício Freire de Melo
- Campus Anísio Teixeira, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45.029-094, Bahia, Brazil
| | - Ana Carla Zarpelon-Schutz
- Campus Toledo, Universidade Federal do Paraná, Toledo 85.919-899, Paraná, Brazil
- Programa de Pós-graduação em Biotecnologia - Setor Palotina, Universidade Federal do Paraná, Palotina 85.950-000, Paraná, Brazil
| | - Kádima Nayara Teixeira
- Campus Toledo, Universidade Federal do Paraná, Toledo 85.919-899, Paraná, Brazil
- Programa Multicêntrico de Pós-graduação em Bioquímica e Biologia Molecular - Setor Palotina, Universidade Federal do Paraná, Palotina 85.950-000, Paraná, Brazil
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17
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Li W, Crouse KK, Alley J, Frisbie RK, Fish SC, Andreyeva TA, Reed LA, Thorn M, DiMaggio G, Donovan CB, Bennett D, Garren J, Oziolor E, Qian J, Newman L, Vargas AP, Kumpf SW, Steyn SJ, Schnute ME, Thorarensen A, Hegen M, Stevens E, Collinge M, Lanz TA, Vincent F, Vincent MS, Berstein G. A Novel C-C Chemoattractant Cytokine (Chemokine) Receptor 6 (CCR6) Antagonist (PF-07054894) Distinguishes between Homologous Chemokine Receptors, Increases Basal Circulating CCR6 + T Cells, and Ameliorates Interleukin-23-Induced Skin Inflammation. J Pharmacol Exp Ther 2023; 386:80-92. [PMID: 37142443 DOI: 10.1124/jpet.122.001452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 03/23/2023] [Accepted: 04/10/2023] [Indexed: 05/06/2023] Open
Abstract
Blocking chemokine receptor C-C chemoattractant cytokine (chemokine) receptor (CCR) 6-dependent T cell migration has therapeutic promise in inflammatory diseases. PF-07054894 is a novel CCR6 antagonist that blocked only CCR6, CCR7, and C-X-C chemoattractant cytokine (chemokine) receptor (CXCR) 2 in a β-arrestin assay panel of 168 G protein-coupled receptors. Inhibition of CCR6-mediated human T cell chemotaxis by (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (PF-07054894) was insurmountable by CCR6 ligand, C-C motif ligand (CCL) 20. In contrast, blockade of CCR7-dependent chemotaxis in human T cells and CXCR2-dependent chemotaxis in human neutrophils by PF-07054894 were surmountable by CCL19 and C-X-C motif ligand 1, respectively. [3H]-PF-07054894 showed a slower dissociation rate for CCR6 than for CCR7 and CXCR2 suggesting that differences in chemotaxis patterns of inhibition could be attributable to offset kinetics. Consistent with this notion, an analog of PF-07054894 with fast dissociation rate showed surmountable inhibition of CCL20/CCR6 chemotaxis. Furthermore, pre-equilibration of T cells with PF-07054894 increased its inhibitory potency in CCL20/CCR6 chemotaxis by 10-fold. The functional selectivity of PF-07054894 for inhibition of CCR6 relative to CCR7 and CXCR2 is estimated to be at least 50- and 150-fold, respectively. When administered orally to naïve cynomolgus monkeys, PF-07054894 increased the frequency of CCR6+ peripheral blood T cells, suggesting that blockade of CCR6 inhibited homeostatic migration of T cells from blood to tissues. PF-07054894 inhibited interleukin-23-induced mouse skin ear swelling to a similar extent as genetic ablation of CCR6. PF-07054894 caused an increase in cell surface CCR6 in mouse and monkey B cells, which was recapitulated in mouse splenocytes in vitro. In conclusion, PF-07054894 is a potent and functionally selective CCR6 antagonist that blocks CCR6-mediated chemotaxis in vitro and in vivo. SIGNIFICANCE STATEMENT: The chemokine receptor, C-C chemoattractant cytokine (chemokine) receptor 6 (CCR6) plays a key role in the migration of pathogenic lymphocytes and dendritic cells into sites of inflammation. (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (PF-07054894) is a novel CCR6 small molecule antagonist that illustrates the importance of binding kinetics in achieving pharmacological potency and selectivity. Orally administered PF-07054894 blocks homeostatic and pathogenic functions of CCR6, suggesting that it is a promising therapeutic agent for the treatment of a variety of autoimmune and inflammatory diseases.
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Affiliation(s)
- Wei Li
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Kimberly K Crouse
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Jennifer Alley
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Richard K Frisbie
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Susan C Fish
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Tatyana A Andreyeva
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Lori A Reed
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Mitchell Thorn
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Giovanni DiMaggio
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Carol B Donovan
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Donald Bennett
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Jeonifer Garren
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Elias Oziolor
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Jesse Qian
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Leah Newman
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Amanda P Vargas
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Steven W Kumpf
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Stefan J Steyn
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Mark E Schnute
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Atli Thorarensen
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Martin Hegen
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Erin Stevens
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Mark Collinge
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Thomas A Lanz
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Fabien Vincent
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Michael S Vincent
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
| | - Gabriel Berstein
- Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Drug Safety Research and Development (L.A.R., G.D., C.B.D., E.O., J.Q., L.N., A.P.V., S.W.K., M.C., T.A.L.), Pfizer, Inc., Groton, Connecticut
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Theofani E, Tsitsopoulou A, Morianos I, Semitekolou M. Severe Asthmatic Responses: The Impact of TSLP. Int J Mol Sci 2023; 24:7581. [PMID: 37108740 PMCID: PMC10142872 DOI: 10.3390/ijms24087581] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/13/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
Asthma is a chronic inflammatory disease that affects the lower respiratory system and includes several categories of patients with varying features or phenotypes. Patients with severe asthma (SA) represent a group of asthmatics that are poorly responsive to medium-to-high doses of inhaled corticosteroids and additional controllers, thus leading in some cases to life-threatening disease exacerbations. To elaborate on SA heterogeneity, the concept of asthma endotypes has been developed, with the latter being characterized as T2-high or low, depending on the type of inflammation implicated in disease pathogenesis. As SA patients exhibit curtailed responses to standard-of-care treatment, biologic therapies are prescribed as adjunctive treatments. To date, several biologics that target specific downstream effector molecules involved in disease pathophysiology have displayed superior efficacy only in patients with T2-high, eosinophilic inflammation, suggesting that upstream mediators of the inflammatory cascade could constitute an attractive therapeutic approach for difficult-to-treat asthma. One such appealing therapeutic target is thymic stromal lymphopoietin (TSLP), an epithelial-derived cytokine with critical functions in allergic diseases, including asthma. Numerous studies in both humans and mice have provided major insights pertinent to the role of TSLP in the initiation and propagation of asthmatic responses. Undoubtedly, the magnitude of TSLP in asthma pathogenesis is highlighted by the fact that the FDA recently approved tezepelumab (Tezspire), a human monoclonal antibody that targets TSLP, for SA treatment. Nevertheless, further research focusing on the biology and mode of function of TSLP in SA will considerably advance disease management.
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Affiliation(s)
- Efthymia Theofani
- Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Aikaterini Tsitsopoulou
- Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Ioannis Morianos
- Host Defense and Fungal Pathogenesis Lab, School of Medicine, University of Crete, 71110 Heraklion, Greece
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300 Heraklion, Greece
| | - Maria Semitekolou
- Laboratory of Immune Regulation and Tolerance, School of Medicine, University of Crete, 71110 Heraklion, Greece
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Sun Z, Liu H, Hu Y, Luo G, Yuan Z, Tu B, Ruan H, Li J, Fan C. STING contributes to trauma-induced heterotopic ossification through NLRP3-dependent macrophage pyroptosis. Clin Immunol 2023; 250:109300. [PMID: 36963448 DOI: 10.1016/j.clim.2023.109300] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 03/05/2023] [Accepted: 03/10/2023] [Indexed: 03/26/2023]
Abstract
Trauma-induced heterotopic ossification (HO) is featured by aberrant bone formation at extra-skeletal site. STING is a master adaptor protein linking cellular damage to immune responses, while its role in HO remains elusive. A murine burn/tenotomy model was used to mimic trauma-induced HO in vivo. We demonstrated elevated STING expression in macrophages in inflammatory stage after burn/tenotomy, and STING inhibition significantly alleviated HO formation. Activated NLRP3-dependent macrophage pyroptosis was also found in inflammatory stage after burn/tenotomy. Either STING or NLRP3 suppression reduced mature HO by weakening macrophage pyroptotic inflammation, while protective effects of STING were abolished by NLRP3 overexpression. Further, in vitro, we also found a prominent STING level in pyroptotic BMDMs. STING suppression relieved macrophage pyroptotic inflammation, while abolished by NLRP3 overexpression. Our results reveal that STING poses regulatory effects on trauma-induced HO formation, via modulating NLRP3-dependent macrophage pyroptosis. Targeting STING-NLRP3 axis represents an attractive approach for trauma-induced HO prevention.
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Affiliation(s)
- Ziyang Sun
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 201306, PR China
| | - Hang Liu
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 201306, PR China
| | - Yuehao Hu
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, PR China
| | - Gang Luo
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 201306, PR China
| | - Zhengqiang Yuan
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 201306, PR China
| | - Bing Tu
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 201306, PR China
| | - Hongjiang Ruan
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 201306, PR China.
| | - Juehong Li
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 201306, PR China.
| | - Cunyi Fan
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 201306, PR China.
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Shnayder NA, Ashhotov AV, Trefilova VV, Nurgaliev ZA, Novitsky MA, Vaiman EE, Petrova MM, Nasyrova RF. Cytokine Imbalance as a Biomarker of Intervertebral Disk Degeneration. Int J Mol Sci 2023; 24:ijms24032360. [PMID: 36768679 PMCID: PMC9917299 DOI: 10.3390/ijms24032360] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/09/2023] [Accepted: 01/17/2023] [Indexed: 01/27/2023] Open
Abstract
The intervertebral disk degeneration (IDD) and its associated conditions are an important problem in modern medicine. The onset of IDD may be in childhood and adolescence in patients with a genetic predisposition. IDD progresses with age, leading to spondylosis, spondylarthrosis, intervertebral disk herniation, and spinal stenosis. The purpose of this review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines in IDD and to appreciate the prognostic value of cytokine imbalance as its biomarker. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to the maintenance or alteration of cytokine balance may be a new key to unlocking the mystery of IDD development and new therapeutic strategies for the treatment of IDD in the setting of acute and chronic inflammation. The presented data support the hypothesis that cytokine imbalance is one of the most important biomarkers of IDD.
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Affiliation(s)
- Natalia A. Shnayder
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Shared Core Facilities “Molecular and Cell Technologies”, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
- Correspondence: (N.A.S.); (R.F.N.); Tel.: +7-(812)-620-0220-7813 (N.A.S. & R.F.N.)
| | - Azamat V. Ashhotov
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
| | | | - Zaitun A. Nurgaliev
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
| | | | - Elena E. Vaiman
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
| | - Marina M. Petrova
- Shared Core Facilities “Molecular and Cell Technologies”, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Regina F. Nasyrova
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Correspondence: (N.A.S.); (R.F.N.); Tel.: +7-(812)-620-0220-7813 (N.A.S. & R.F.N.)
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Bryant N, Muehling LM. T-cell responses in asthma exacerbations. Ann Allergy Asthma Immunol 2022; 129:709-718. [PMID: 35918022 PMCID: PMC9987567 DOI: 10.1016/j.anai.2022.07.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/22/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Asthma is a chronic lung disease comprising multiple endotypes and characterized by periodic exacerbations. A diverse array of T cells has been found to contribute to all endotypes of asthma in pathogenic and regulatory roles. Here, we review the contributions of CD4+, CD8+, and unconventional T cells in allergic and nonallergic asthma. DATA SOURCES Review of published literature pertaining to conventional and unconventional T-cell types in asthma. STUDY SELECTIONS Recent peer-reviewed articles pertaining to T cells in asthma, with additional peer-reviewed studies for context. RESULTS Much research in asthma has focused on the roles of CD4+ TH cells. Roles for TH2 cells in promoting allergic asthma pathogenesis have been well-described, and the recent description of pathogenic TH2A cells provides additional insight into these responses. Other TH types, notably TH1 and TH17, have been linked to neutrophilic and steroid-resistant asthma phenotypes. Beyond CD4+ T cells, CD8+ Tc2 cells are also strongly associated with allergic asthma. An emerging area for study is unconventional T-cell types, including γδT, invariant natural killer T, and mucosal-associated invariant T cells. Although data in asthma remain limited for these cells, their ability to bridge innate and adaptive responses likely makes them key players in asthma. A number of asthma therapies target T-cell responses, and, although data are limited, they seem to modulate T-cell populations. CONCLUSION Given the diversity and heterogeneity of asthma and T-cell responses, there remain many rich avenues for research to better understand the pathogenesis of asthma. Despite the breadth of T cells in asthma, approved therapeutics remain limited to TH2 networks.
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Affiliation(s)
- Naomi Bryant
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Lyndsey M Muehling
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
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Baker R, Hontecillas R, Tubau-Juni N, Leber AJ, Kale S, Bassaganya-Riera J. Computational modeling of complex bioenergetic mechanisms that modulate CD4+ T cell effector and regulatory functions. NPJ Syst Biol Appl 2022; 8:45. [DOI: 10.1038/s41540-022-00263-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 11/11/2022] [Indexed: 11/24/2022] Open
Abstract
AbstractWe built a computational model of complex mechanisms at the intersection of immunity and metabolism that regulate CD4+ T cell effector and regulatory functions by using coupled ordinary differential equations. The model provides an improved understanding of how CD4+ T cells are shaping the immune response during Clostridioides difficile infection (CDI), and how they may be targeted pharmacologically to produce a more robust regulatory (Treg) response, which is associated with improved disease outcomes during CDI and other diseases. LANCL2 activation during CDI decreased the effector response, increased regulatory response, and elicited metabolic changes that favored Treg. Interestingly, LANCL2 activation provided greater immune and metabolic modulation compared to the addition of exogenous IL-2. Additionally, we identified gluconeogenesis via PEPCK-M as potentially responsible for increased immunosuppressive behavior in Treg cells. The model can perturb immune signaling and metabolism within a CD4+ T cell and obtain clinically relevant outcomes that help identify novel drug targets for infectious, autoimmune, metabolic, and neurodegenerative diseases.
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Qu L, Matz AJ, Karlinsey K, Cao Z, Vella AT, Zhou B. Macrophages at the Crossroad of Meta-Inflammation and Inflammaging. Genes (Basel) 2022; 13:2074. [PMID: 36360310 PMCID: PMC9690997 DOI: 10.3390/genes13112074] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/24/2022] [Accepted: 11/07/2022] [Indexed: 08/29/2023] Open
Abstract
Macrophages are central players in systemic inflammation associated with obesity and aging, termed meta-inflammation and inflammaging. Activities of macrophages elicited by the two chronic conditions display shared and distinct patterns mechanistically, resulting in multifaceted actions for their pathogenic roles. Drastically expanded tissue macrophage populations under obesity and aging stress attribute to both enhanced recruitment and local expansion. Importantly, molecular networks governing the multifaceted actions of macrophages are directly altered by environmental cues and subsequently contribute to metabolic reprogramming, resulting in meta-inflammation in obesity or inflammaging in aging. In this review, we will summarize how meta-inflammation and inflammaging affect macrophages and the molecular mechanisms involved in these processes.
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Affiliation(s)
- Lili Qu
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
| | - Alyssa J. Matz
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
| | - Keaton Karlinsey
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
| | - Ziming Cao
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
| | - Anthony T. Vella
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
- Institute for Systems Genomics, University of Connecticut, Farmington, CT 06030, USA
| | - Beiyan Zhou
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
- Institute for Systems Genomics, University of Connecticut, Farmington, CT 06030, USA
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Bartziokas K, Fouka E, Loukides S, Steiropoulos P, Bakakos P, Papaioannou AI. IL-26 in the Lung and Its Role in COPD Inflammation. J Pers Med 2022; 12:jpm12101685. [PMID: 36294822 PMCID: PMC9605572 DOI: 10.3390/jpm12101685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 10/02/2022] [Accepted: 10/07/2022] [Indexed: 11/05/2022] Open
Abstract
IL-26 is a cytokine expressed by infiltrating pro-inflammatory IL-17-producing T cells in the tissues of patients with chronic lung inflammation. IL-26 induces the chemotactic response of human neutrophils to bacteria and other inflammatory stimuli. In recent years, the innovative properties of IL-26 have been described. Studies have shown that, as DNA is released from damaged cells, it binds to IL-26, which plays the role of a carrier molecule for extracellular DNA, further contributing to its binding to the site of inflammation. This mechanism of action indicates that IL-26 may serve both as a driver as well as a stimulus of the inflammatory process, leading to the installation of a noxious amplification loop and, eventually, persistent inflammation. IL-26 also demonstrates direct antimicrobial effects derived from its capability to create pores and disrupt bacterial membranes, as indicated by the presence of membrane blebs on the surface of the bacteria and cytosolic leakage pores in bacterial walls, produced in response to microbial stimuli in human airways by several different immune and structural cells. Surprisingly, while this particular cytokine induces the gathering of neutrophils in areas of infection, it also exhibits inhibitory and pro-inflammatory effects on airway epithelial and immune cells. These remarkable effects underline the necessity of a better understating of its biological behavior and its role in the pathophysiology and disease burden in several smoking-related airway inflammatory disorders, such as Chronic Obstructive Pulmonary Disease (COPD) and chronic bronchitis. In this review, we aim to discuss the current role of IL-26 in the lung, with an emphasis on systemic inflammation in patients suffering from COPD and chronic bronchitis.
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Affiliation(s)
| | - Evangelia Fouka
- Respiratory Medicine Department, George Papanikolaou Hospital, University of Thessaloniki, 57010 Thessaloniki, Greece
| | - Stelios Loukides
- 2nd Respiratory Medicine Department, “Attikon” University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Paschalis Steiropoulos
- Department of Respiratory Medicine, Medical School, University General Hospital Dragana, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Petros Bakakos
- 1st University Department of Respiratory Medicine, “Sotiria” Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Andriana I. Papaioannou
- 1st University Department of Respiratory Medicine, “Sotiria” Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
- Correspondence: ; Tel.: +30-21-0583-1163; Fax: +30-21-0583-1184
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Aoki C, Imai K, Mizutani T, Sugiyama D, Miki R, Koya Y, Kobayashi T, Ushida T, Iitani Y, Nakamura N, Owaki T, Nishikawa H, Toyokuni S, Kajiyama H, Kotani T. Molecular hydrogen has a positive impact on pregnancy maintenance through enhancement of mitochondrial function and immunomodulatory effects on T cells. Life Sci 2022; 308:120955. [PMID: 36115583 DOI: 10.1016/j.lfs.2022.120955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/30/2022] [Accepted: 09/09/2022] [Indexed: 10/31/2022]
Abstract
AIMS Molecular hydrogen (H2) has attracted growing interest because of its implications in various diseases. However, the molecular mechanisms underlying the remarkable effect of a small amount of H2 remain elusive. No knowledge has been available on the role of H2 in the etiology of pregnancy disorders or its direct influence on human immune cells. Since maternal immunity, T cells in particular, plays a critical role in pregnancy maintenance. We investigated the effects of H2 on T cells and its relation to preterm birth (PTB). MAIN METHODS Exhaled H2 concentrations in pregnant women were measured and correlated with cytokine concentrations in maternal and umbilical cord blood. H2 was added to T cells collected from healthy donors, and differentiation and proliferation were examined. Energy metabolism was also examined. H2 was administered to mice and cytokine expression was compared. KEY FINDINGS Our prospective observational study revealed that maternal production of H2 is significantly lower in pregnant women with PTB, suggesting its potential as a biomarker for predicting PTB. We found that H2 has clear associations with several maternal cytokines, and acts as an immunomodulator by exerting mitochondrial function in human T cells. Moreover, in vivo administration of H2 to pregnant mice regulated inflammatory responses and reduced PTB caused by T cell activation, which further supports the notion that H2 may contribute to prolonged gestation through its immunomodulatory effect. SIGNIFICANCE Measuring maternal H2-production could be a potential clinical tool in the management of PTB, and H2 may have positive impact on pregnancy maintenance.
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Affiliation(s)
- Chieko Aoki
- Department of Obstetrics and Gynecology, Japan
| | - Kenji Imai
- Department of Obstetrics and Gynecology, Japan.
| | - Teruyuki Mizutani
- Department of Obstetrics and Gynecology, Japan; Department of Immunology, Japan
| | | | - Rika Miki
- Laboratory of Bell Research Centre-Department of Obstetrics and Gynecology Collaborative Research, Bell Research Centre for Reproductive Health and Cancer, Department of Reproduction, Japan
| | - Yoshihiro Koya
- Laboratory of Bell Research Centre-Department of Obstetrics and Gynecology Collaborative Research, Bell Research Centre for Reproductive Health and Cancer, Department of Reproduction, Japan
| | | | | | | | | | - Taro Owaki
- Department of Obstetrics and Gynecology, Japan
| | - Hiroyoshi Nishikawa
- Department of Immunology, Japan; Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Shinya Toyokuni
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Noack M, Miossec P. Synoviocytes and skin fibroblasts show opposite effects on IL-23 production and IL-23 receptor expression during cell interactions with immune cells. Arthritis Res Ther 2022; 24:220. [PMID: 36088336 PMCID: PMC9463863 DOI: 10.1186/s13075-022-02904-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 08/24/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The IL-23/IL-17 axis is involved in inflammatory diseases including arthritis and psoriasis. However, the response to IL-23 or IL-17 inhibitors is different depending on the disease. The aim was to compare the effects of interactions between immune and stromal cells on the IL-23 axis to understand these differences.
Methods
Peripheral blood mononuclear cells were co-cultured with RA synoviocytes or Pso skin fibroblasts, with or without phytohemagglutinin, IL-23, or anti-IL-23 antibody. Production of IL-6, IL-1β, IL-23, IL-17, IL-12, and IFNγ was measured by ELISA. IL-23 and cytokine receptor gene expression (IL-17RA, IL-17RC, IL-12Rβ1, IL-12Rβ2, and IL-23R) was analyzed by RT-qPCR. IL-12Rβ1 and IL-23R subunits were analyzed by flow cytometry.
Results
The production of IL-6, IL-1β, IL-17, IL-12, and IFNγ with synoviocytes or skin fibroblasts was rather similar, and cell interactions with immune cells increased their production, specifically that of IL-17. A major difference was observed for IL-23. Interactions with synoviocytes but not with skin fibroblasts decreased IL-23 secretion while mRNA level was increased, mainly with synoviocytes, reflecting a major consumption difference. IL-23 addition had only one effect, the increase of IL-17 secretion. Cell activation induced similar effects on cytokine receptor gene expression in co-cultures with synoviocytes or skin fibroblasts. The key difference was the cell interaction effects depending on the stromal cell origin. Interactions with synoviocytes increased the expression of both IL-23 receptor subunits at mRNA levels and IL-23R at the surface expression level while interactions with skin fibroblasts decreased their expression at the mRNA level and had no effect at the surface expression level.
Conclusion
Interactions between immune and stromal cells are crucial in cytokine production and their receptor expression. The origin of stromal cells had a major influence on the production of IL-23 and its receptor expression. Such differences may explain part of the heterogeneity in treatment response.
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The Diagnostic Utility of Interleukin-13 and Interleukin-17A using the ELISA Technique in Asthmatic Children. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2022. [DOI: 10.22207/jpam.16.3.22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The heterogeneous etiology of asthma makes its diagnosis complicated. Measurement of cytokine levels could be relevant in determining the asthma phenotype, predicting severity, and identifying the treatment type. Enzyme-linked immunosorbent assay (ELISA) is one of the most reliable methods, with high sensitivity and specificity. This study aimed to determine the accuracy and utility of interleukin (IL)-13 and IL-17 A in diagnosing children with asthma. A total of 74 asthmatic and 75 healthy children were enrolled in this case-control study between 10/2019 and 3/2021. Sera were collected and analyzed for IL-13 and IL-17A using ELISA. Diagnostic utility assessment was performed using receiver operating characteristic (ROC) analysis. The results showed that both cytokines had a significant capacity to differentiate patients with asthma from the control group. The sensitivity and specificity for IL-17A were 97.3% and 52.0%, respectively, whereas for IL-13 it was 81.1% and 52.0%, respectively. Positive predictive values (PPV) were 66.7% and 62.5% for IL-17A and IL-13, respectively. In conclusion, although both biomarkers had low specificity, IL-17A was more sensitive in differentiating children with asthma from those in the control group and had a higher sensitivity rate than IL-13.
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28
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Luo W, Hu J, Xu W, Dong J. Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma. Front Immunol 2022; 13:974066. [PMID: 36032162 PMCID: PMC9411752 DOI: 10.3389/fimmu.2022.974066] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 07/28/2022] [Indexed: 12/24/2022] Open
Abstract
Immune response in the asthmatic respiratory tract is mainly driven by CD4+ T helper (Th) cells, represented by Th1, Th2, and Th17 cells, especially Th2 cells. Asthma is a heterogeneous and progressive disease, reflected by distinct phenotypes orchestrated by τh2 or non-Th2 (Th1 and Th17) immune responses at different stages of the disease course. Heterogeneous cytokine expression within the same Th effector state in response to changing conditions in vivo and interlineage relationship among CD4+ T cells shape the complex immune networks of the inflammatory airway, making it difficult to find one panacea for all asthmatics. Here, we review the role of three T helper subsets in the pathogenesis of asthma from different stages, highlighting timing is everything in the immune system. We also discuss the dynamic topography of Th subsets and pathogenetic memory Th cells in asthma.
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Affiliation(s)
- Weihang Luo
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China
- Institutes of Integrative Medicine, Fudan University, Shanghai, China
| | - Jindong Hu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Weifang Xu
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, China
- *Correspondence: Jingcheng Dong, ; Weifang Xu,
| | - Jingcheng Dong
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China
- Institutes of Integrative Medicine, Fudan University, Shanghai, China
- *Correspondence: Jingcheng Dong, ; Weifang Xu,
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29
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Cahill KM, Johnson TK, Perveen Z, Schexnayder M, Xiao R, Heffernan LM, Langohr IM, Paulsen DB, Penn AL, Noël A. In utero exposures to mint-flavored JUUL aerosol impair lung development and aggravate house dust mite-induced asthma in adult offspring mice. Toxicology 2022; 477:153272. [PMID: 35878681 DOI: 10.1016/j.tox.2022.153272] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 07/04/2022] [Accepted: 07/21/2022] [Indexed: 11/18/2022]
Abstract
There are few reports concerning electronic nicotine delivery system (ENDS) use during pregnancy and no studies on asthma in prenatally JUUL-exposed offspring. Here, we tested the hypothesis that in utero JUUL exposure causes unfavorable birth outcomes and lasting pulmonary health effects in adult offspring. BALB/c dams were exposed to either air or mint-flavored JUUL aerosol, 1-hr/d, 20 consecutive days during gestation. Offspring were sacrificed on post-natal day (PND) 0 or at 11-week of age, following house dust mite (HDM) challenge. Gene expression was assessed in the uterine/placental tissue of the dams and lung responses were assessed in offspring at PND0 and at 11 weeks of age. JUUL-exposed offspring exhibited decreased body weights and lengths at PND0. These birth outcomes were accompanied by dysregulation of 54 genes associated with hypoxia and oxidative stress in the uterine/placental tissues of JUUL-exposed dams, as well as 24 genes in the lungs of the offspring related to Wnt signaling, plus 9 genes related to epigenetics, and 7 genes related to inflammation. At 11 weeks of age, JUUL + HDM exposed mice exhibited pulmonary inflammation when compared to their respective air + HDM controls. Additionally, the JUUL + HDM exposure dysregulated several genes associated with allergies and asthma. Further, the JUUL + HDM females showed decreased methylation of the promoter region of the Il10ra gene. Taken together, our mouse model shows that inhalation of JUUL aerosols during pregnancy affects the intrauterine environment, impairs lung development, and heightens the effects of allergic airway responses later in life.
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Affiliation(s)
- Kerin M Cahill
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Trenton K Johnson
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Zakia Perveen
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Matthew Schexnayder
- Lincoln Memorial University, College of Veterinary Medicine, 6965 Cumberland Gap Parkway, Harrogate, TN, USA
| | - Rui Xiao
- Department of Anesthesiology, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA
| | - Linda M Heffernan
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Ingeborg M Langohr
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Daniel B Paulsen
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Arthur L Penn
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Alexandra Noël
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
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Howard FHN, Kwan A, Winder N, Mughal A, Collado-Rojas C, Muthana M. Understanding Immune Responses to Viruses-Do Underlying Th1/Th2 Cell Biases Predict Outcome? Viruses 2022; 14:1493. [PMID: 35891472 PMCID: PMC9324514 DOI: 10.3390/v14071493] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/04/2022] [Accepted: 07/06/2022] [Indexed: 12/15/2022] Open
Abstract
Emerging and re-emerging viral diseases have increased in number and geographical extent during the last decades. Examples include the current COVID-19 pandemic and the recent epidemics of the Chikungunya, Ebola, and Zika viruses. Immune responses to viruses have been well-characterised within the innate and adaptive immunity pathways with the outcome following viral infection predominantly attributed to properties of the virus and circumstances of the infection. Perhaps the belief that the immune system is often considered as a reactive component of host defence, springing into action when a threat is detected, has contributed to a poorer understanding of the inherent differences in an individual's immune system in the absence of any pathology. In this review, we focus on how these host factors (age, ethnicity, underlying pathologies) may skew the T helper cell response, thereby influencing the outcome following viral infection but also whether we can use these inherent biases to predict patients at risk of a deviant response and apply strategies to avoid or overcome them.
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Affiliation(s)
- Faith H. N. Howard
- Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK; (A.K.); (N.W.); (A.M.); (C.C.-R.); (M.M.)
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31
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Magnusson JM, Ericson P, Tengvall S, Stockfelt M, Brundin B, Lindén A, Riise GC. Involvement of IL-26 in bronchiolitis obliterans syndrome but not in acute rejection after lung transplantation. Respir Res 2022; 23:108. [PMID: 35501858 PMCID: PMC9063324 DOI: 10.1186/s12931-022-02036-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 04/25/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The main long-term complication after lung transplantation is bronchiolitis obliterans syndrome (BOS), a deadly condition in which neutrophils may play a critical pathophysiological role. Recent studies show that the cytokine interleukin IL-26 can facilitate neutrophil recruitment in response to pro-inflammatory stimuli in the airways. In this pilot study, we characterized the local involvement of IL-26 during BOS and acute rejection (AR) in human patients. METHOD From a biobank containing bronchoalveolar lavage (BAL) samples from 148 lung transplant recipients (LTR), clinically-matched patient pairs were identified to minimize the influence of clinical confounders. We identified ten pairs (BOS/non-BOS) with BAL samples harvested on three occasions for our longitudinal investigation and 12 pairs of patients with and without AR. The pairs were matched for age, gender, preoperative diagnosis, type of and time after surgery. Extracellular IL-26 protein was quantified in cell-free BAL samples using an enzyme-linked immunosorbent assay. Intracellular IL-26 protein in BAL cells was determined using immunocytochemistry (ICC) and flow cytometry. RESULTS The median extracellular concentration of IL-26 protein was markedly increased in BAL samples from patients with BOS (p < 0.0001) but not in samples from patients with AR. Intracellular IL-26 protein was confirmed in alveolar macrophages and lymphocytes (through ICC and flow cytometry) among BAL cells obtained from BOS patients. CONCLUSIONS Local IL-26 seems to be involved in BOS but not AR, and macrophages as well as lymphocytes constitute cellular sources in this clinical setting. The enhancement of extracellular IL-26 protein in LTRs with BOS warrants further investigation of its potential as a target for diagnosing, monitoring, and treating BOS.
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Affiliation(s)
- Jesper M Magnusson
- Department of Respiratory Medicine, Institute of Medicine Sahlgrenska Academy at the University of Gothenburg, Bruna stråket 11, 41345, Gothenburg, Sweden.
| | - Petrea Ericson
- Department of Respiratory Medicine, Institute of Medicine Sahlgrenska Academy at the University of Gothenburg, Bruna stråket 11, 41345, Gothenburg, Sweden
| | - Sara Tengvall
- Department of Respiratory Medicine, Institute of Medicine Sahlgrenska Academy at the University of Gothenburg, Bruna stråket 11, 41345, Gothenburg, Sweden.,Division for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Marit Stockfelt
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Bettina Brundin
- Division for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anders Lindén
- Division for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
| | - Gerdt C Riise
- Department of Respiratory Medicine, Institute of Medicine Sahlgrenska Academy at the University of Gothenburg, Bruna stråket 11, 41345, Gothenburg, Sweden
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Impact of body mass index on omalizumab response in adults with moderate-to-severe allergic asthma. Ann Allergy Asthma Immunol 2022; 128:553-560. [PMID: 35101644 DOI: 10.1016/j.anai.2022.01.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/10/2022] [Accepted: 01/11/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND Effectiveness of asthma treatment, including biologics, may be different in patients with higher body mass index (BMI). OBJECTIVE To evaluate response to omalizumab (dosed by serum immunoglobulin E level and weight) by BMI category. METHODS Pooled data from 2 randomized, double-blind, placebo-controlled studies of adults with moderate-to-severe allergic asthma were analyzed by BMI category (<25 kg/m2 [normal or underweight], n = 397; 25 to <30 kg/m2 [overweight], n = 330; ≥ 30 kg/m2 [obese], n = 268). Placebo-adjusted exacerbation rate reductions were evaluated by Poisson regression modeling. Changes from baseline in forced expiratory volume in 1 second, beclomethasone dipropionate (BDP) dose, Total Asthma Symptom Score, and Asthma Quality of Life Questionnaire were evaluated by analysis of covariance. RESULTS Greater placebo-adjusted exacerbation rate reductions (95% confidence interval) were observed with increasing BMI (normal or underweight, -37.4% [-69.0% to 26.8%]; overweight, -52.7% [-78.4% to 3.7%]; obese, -71.9% [-86.9% to -39.5%]). There were no differences in forced expiratory volume in 1 second improvement between BMI categories at week 16 (normal or underweight, 76.2 [5.3-147.1] mL; overweight, 98.1 [13.9-182.4] mL; obese, 69.1 [-18.9 to 157.2] mL). No differences in BDP dose reduction (µg) were noted between BMI categories (normal or underweight, 23.0 [15.7-30.3]; overweight, 22.5 [13.5-31.5]; obese, 16.6 [5.8-27.3]). Fewer patients in the higher BMI categories eliminated BDP use. There were trends for smaller improvements with higher BMI in Total Asthma Symptom Score (normal/underweight, -0.52 [-0.82 to -0.22]; overweight, -0.50 [-0.80 to -0.20]; obese, -0.39 [-0.77 to 0.00]) and Asthma Quality of Life Questionnaire (normal or underweight, 0.34 [0.16-0.52]; overweight, 0.34 [0.13-0.55]; obese, 0.15 [-0.08 to 0.39]). CONCLUSION Omalizumab provides benefit to patients with moderate-to-severe allergic asthma, regardless of BMI. TRIAL REGISTRATION Studies 008/009 were conducted before clinical trial registration was required, and therefore clinical trial registration numbers are not available.
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Vasconcelos DP, Jabangwe C, Lamghari M, Alves CJ. The Neuroimmune Interplay in Joint Pain: The Role of Macrophages. Front Immunol 2022; 13:812962. [PMID: 35355986 PMCID: PMC8959978 DOI: 10.3389/fimmu.2022.812962] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/15/2022] [Indexed: 12/29/2022] Open
Abstract
Chronic pain associated with joint disorders, such as rheumatoid arthritis (RA), osteoarthritis (OA) and implant aseptic loosening (AL), is a highly debilitating symptom that impacts mobility and quality of life in affected patients. The neuroimmune crosstalk has been demonstrated to play a critical role in the onset and establishment of chronic pain conditions. Immune cells release cytokines and immune mediators that can activate and sensitize nociceptors evoking pain, through interaction with receptors in the sensory nerve terminals. On the other hand, sensory and sympathetic nerve fibers release neurotransmitters that bind to their specific receptor expressed on surface of immune cells, initiating an immunomodulatory role. Macrophages have been shown to be key players in the neuroimmune crosstalk. Moreover, macrophages constitute the dominant immune cell population in RA, OA and AL. Importantly, the targeting of macrophages can result in anti-nociceptive effects in chronic pain conditions. Therefore, the aim of this review is to discuss the nature and impact of the interaction between the inflammatory response and nerve fibers in these joint disorders regarding the genesis and maintenance of pain. The role of macrophages is highlighted. The alteration in the joint innervation pattern and the inflammatory response are also described. Additionally, the immunomodulatory role of sensory and sympathetic neurotransmitters is revised.
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Affiliation(s)
- Daniela P Vasconcelos
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto- Associação, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Clive Jabangwe
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto- Associação, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,Faculdade de Engenharia, Universidade do Porto, Porto, Portugal
| | - Meriem Lamghari
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto- Associação, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.,Instituto Ciências Biomédicas Abel Salazar, Universidade de Porto, Porto, Portugal
| | - Cecília J Alves
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto- Associação, Porto, Portugal.,Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
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Muench DE, Sun Z, Sharma A, Tang C, Crampton JS, Lao C, Kersjes K, Chang W, Na S. A Pathogenic Th17/CD38 + Macrophage Feedback Loop Drives Inflammatory Arthritis through TNF-α. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1315-1328. [PMID: 35197330 DOI: 10.4049/jimmunol.2101025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/04/2022] [Indexed: 12/29/2022]
Abstract
The pathobiology of rheumatoid inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis, involves the interplay between innate and adaptive immune components and resident synoviocytes. Single-cell analyses of patient samples and relevant mouse models have characterized many cellular subsets in RA. However, the impact of interactions between cell types is not fully understood. In this study, we temporally profiled murine arthritic synovial isolates at the single-cell level to identify perturbations similar to those found in human RA. Notably, murine macrophage subtypes like those found in RA patients were expanded in arthritis and linked to promoting the function of Th17 cells in the joint. In vitro experiments identified a capacity for murine macrophages to maintain the functionality and expansion of Th17 cells. Reciprocally, murine Th17 cell-derived TNF-α induced CD38+ macrophages that enhanced Th17 functionality. Murine synovial CD38+ macrophages were expanded during arthritis, and their depletion or blockade via TNF-α neutralization alleviated disease while reducing IL-17A-producing cells. These findings identify a cellular feedback loop that promotes Th17 cell pathogenicity through TNF-α to drive inflammatory arthritis.
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Affiliation(s)
- David E Muench
- Immunology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, San Diego, CA
| | - Zhe Sun
- Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN; and
| | - Anchal Sharma
- Research Information and Digital Solutions, Lilly Research Laboratories, Eli Lilly and Company, New York, NY
| | - Crystal Tang
- Immunology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, San Diego, CA
| | - Jordan S Crampton
- Immunology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, San Diego, CA
| | - Christopher Lao
- Immunology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, San Diego, CA
| | - Kara Kersjes
- Immunology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, San Diego, CA
| | - William Chang
- Immunology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, San Diego, CA
| | - Songqing Na
- Immunology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, San Diego, CA;
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Suyama K, Sakai D, Watanabe M. The Role of IL-17-Mediated Inflammatory Processes in the Pathogenesis of Intervertebral Disc Degeneration and Herniation: A Comprehensive Review. Front Cell Dev Biol 2022; 10:857164. [PMID: 35309927 PMCID: PMC8927779 DOI: 10.3389/fcell.2022.857164] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 02/17/2022] [Indexed: 12/12/2022] Open
Abstract
It has been reported that degenerated and herniated lumbar intervertebral discs show high expression of IL-17, suggesting that local immune reactions occur in patients with low back pain. While clinical sample analyses from different laboratories confirm this, it is not deeply not known on how IL-17 is induced in the pathology and their interactions with other inflammatory responses. This conscience review organizes current laboratory findings on this topic and present trajectory for full understanding on the role of IL-17 in pathology of intervertebral disc disease.
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Affiliation(s)
- Kaori Suyama
- Department of Anatomy and Cellular Biology, Basic Medical Science, Tokai University School of Medicine, Isehara, Japan
| | - Daisuke Sakai
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Japan
- *Correspondence: Daisuke Sakai,
| | - Masahiko Watanabe
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Japan
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36
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Pan S, Wu YJ, Zhang SS, Cheng XP, Olatunji OJ, Yin Q, Zuo J. The Effect of α7nAChR Signaling on T Cells and Macrophages and Their Clinical Implication in the Treatment of Rheumatic Diseases. Neurochem Res 2022; 47:531-544. [PMID: 34783974 DOI: 10.1007/s11064-021-03480-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 11/02/2021] [Accepted: 11/05/2021] [Indexed: 10/19/2022]
Abstract
Rheumatoid arthritis (RA) is one of the most common autoimmune disease and until now, the etiology and pathogenesis of RA is not fully understood, although dysregulation of immune cells is one of the leading cause of RA-related pathological changes. Based on current understanding, the priority of anti-rheumatic treatments is to restore immune homeostasis. There are several anti-rheumatic drugs with immunomodulatory effects available nowadays, but most of them have obvious safety or efficacy shortcomings. Therefore, the development of novel anti-rheumatic drugs is still in urgently needed. Cholinergic anti-inflammatory pathway (CAP) has been identified as an important aspect of the so-called neuro-immune regulation feedback, and the interaction between acetylcholine and alpha 7 nicotinic acetylcholine receptor (α7nAChR) serves as the foundation for this signaling. Consistent to its immunomodulatory functions, α7nAChR is extensively expressed by immune cells. Accordingly, CAP activation greatly affects the differentiation and function of α7nAChR-expressing immune cells. As a result, targeting α7nAChR will bring profound therapeutic impacts on the treatment of inflammatory diseases like RA. RA is widely recognized as a CD4+ T cells-driven disease. As a major component of innate immunity, macrophages also significantly contribute to RA-related immune abnormalities. Theoretically, manipulation of CAP in immune cells is a feasible way to treat RA. In this review, we summarized the roles of different T cells and macrophages subsets in the occurrence and progression of RA, and highlighted the immune consequences of CAP activation in these cells under RA circumstances. The in-depth discussion is supposed to inspire the development of novel cell-specific CAP-targeting anti-rheumatic regimens.
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Affiliation(s)
- Shu Pan
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, China
| | - Yi-Jin Wu
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, China
| | - Sa-Sa Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, China
| | - Xiu-Ping Cheng
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
| | - Opeyemi Joshua Olatunji
- Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90110, Thailand
| | - Qin Yin
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China.
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China.
| | - Jian Zuo
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China.
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, China.
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Ogundepo S, Chiamaka AM, Olatinwo M, Adepoju D, Aladesanmi MT, Celestine UO, Ali KC, Umezinwa OJ, Olasore J, Alausa A. The role of diosgenin in crohn’s disease. CLINICAL PHYTOSCIENCE 2022. [DOI: 10.1186/s40816-022-00338-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
AbstractInflammatory bowel disease (IBD) is a chronic idiopathic inflammation that can grossly affect the entire gastrointestinal tract (GIT) from the mouth to the anus. Crohn’s disease is the most known type of IBD and has been the focus of attention due to its increase in prevalence worldwide. Although the etiology is yet to be elucidated, recent studies have pointed out Crohn’s disease to arise from a complex interaction between environmental influences, genetic predisposition, and altered gut microbiota, resulting in dysregulated adaptive and innate responses. The presenting hallmarks of Crohn’s disease may include weight loss, nausea, vomiting, abdominal pain, diarrhea, fever, or chills. Treatment is usually done with many approved immunosuppressive drugs and surgery. However, a promising avenue from natural compounds is a safer therapy due to its safe natural active ingredients and the strong activity it shows in the treatment and management of diseases. Diosgenin, “a major biologically active natural steroidal sapogenin found in Chinese yam,” has been widely reported as a therapeutic agent in the treatment of various classes of disorders such as hyperlipidemia, inflammation, diabetes, cancer, infection, and immunoregulation. In this review, an analysis of literature data on diosgenin employed as a therapeutic agent for the treatment of Crohn’s disease is approached, to strengthen the scientific database and curtail the dreadful impact of Crohn’s disease.
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Topical Treatment of Colquhounia Root Relieves Skin Inflammation and Itch in Imiquimod-Induced Psoriasiform Dermatitis in Mice. Mediators Inflamm 2022; 2022:5782922. [PMID: 35069008 PMCID: PMC8767412 DOI: 10.1155/2022/5782922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 12/15/2021] [Accepted: 12/27/2021] [Indexed: 11/17/2022] Open
Abstract
Itch is one of the major clinical manifestations of psoriasis, which is closely related with neurogenic inflammation and difficult to control. Colquhounia Root (CR) is a Chinese herb exhibiting broad bioactivities on anti-inflammation. This study was designed to explore the antipsoriatic and anti-itch potential of CR and its underlying mechanisms. Mice in a model of imiquimod-induced psoriasiform dermatitis were treated topically with CR for 7 days, and the severity of skin lesions and itch was significantly ameliorated. CR reduced the inflammatory cell infiltration, as well as mast cells in skins. Particularly, the expression of inflammatory cytokines and chemokine including Il17a, Il22, and Ccl20 and itch-related molecules such as SP, CGRP, and NGF in lesions were decreased in diseased mice upon application with CR. The normal human epidermal keratinocytes were stimulated with the M5 cytokine cocktail, the mixture of IL-17A, IL-22, Oncostatin M, IL-1α, and TNF-α, and cell viability and mRNA expression levels of inflammatory factors and itch-related molecules were measured after being treated with CR. We found that CR inhibited both cell hyperproliferation and overexpression of inflammatory cytokines and itch-related molecules in vitro. Altogether, we conclude that CR relieves psoriatic lesions and itch via controlling immunological and neurogenic inflammation.
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Hu Y, Ye Z, Wu M, She Y, Li L, Xu Y, Qin K, Hu Z, Yang M, Lu F, Ye Q. The Communication Between Intestinal Microbiota and Ulcerative Colitis: An Exploration of Pathogenesis, Animal Models, and Potential Therapeutic Strategies. Front Med (Lausanne) 2021; 8:766126. [PMID: 34966755 PMCID: PMC8710685 DOI: 10.3389/fmed.2021.766126] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 11/18/2021] [Indexed: 12/12/2022] Open
Abstract
Ulcerative Colitis (UC) is a chronic inflammatory bowel disease. The prolonged course of UC and the lack of effective treatment management make it difficult to cure, affecting the health and life safety of patients. Although UC has received more attention, the etiology and pathogenesis of UC are still unclear. Therefore, it is urgent to establish an updated and comprehensive understanding of UC and explore effective treatment strategies. Notably, sufficient evidence shows that the intestinal microbiota plays an important role in the pathogenesis of UC, and the treating method aimed at improving the balance of the intestinal microbiota exhibits a therapeutic potential for UC. This article reviews the relationship between the genetic, immunological and microbial risk factors with UC. At the same time, the UC animal models related to intestinal microbiota dysbiosis induced by chemical drugs were evaluated. Finally, the potential value of the therapeutic strategies for restoring intestinal microbial homeostasis and treating UC were also investigated. Comprehensively, this study may help to carry out preclinical research, treatment theory and methods, and health management strategy of UC, and provide some theoretical basis for TCM in the treatment of UC.
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Affiliation(s)
- Yu Hu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhen Ye
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingquan Wu
- Department of Pharmacy, Sichuan Provincial Orthopedic Hospital, Chengdu, China
| | - Yingqi She
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Linzhen Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yujie Xu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Kaihua Qin
- Health Preservation and Rehabilitation College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhipeng Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Maoyi Yang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fating Lu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiaobo Ye
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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40
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Wu Y, Zeng Z, Guo Y, Song L, Weatherhead JE, Huang X, Zeng Y, Bimler L, Chang CY, Knight JM, Valladolid C, Sun H, Cruz MA, Hube B, Naglik JR, Luong AU, Kheradmand F, Corry DB. Candida albicans elicits protective allergic responses via platelet mediated T helper 2 and T helper 17 cell polarization. Immunity 2021; 54:2595-2610.e7. [PMID: 34506733 DOI: 10.1016/j.immuni.2021.08.009] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 05/19/2021] [Accepted: 08/10/2021] [Indexed: 12/24/2022]
Abstract
Fungal airway infection (airway mycosis) is an important cause of allergic airway diseases such as asthma, but the mechanisms by which fungi trigger asthmatic reactions are poorly understood. Here, we leverage wild-type and mutant Candida albicans to determine how this common fungus elicits characteristic Th2 and Th17 cell-dependent allergic airway disease in mice. We demonstrate that rather than proteinases that are essential virulence factors for molds, C. albicans instead promoted allergic airway disease through the peptide toxin candidalysin. Candidalysin activated platelets through the Von Willebrand factor (VWF) receptor GP1bα to release the Wnt antagonist Dickkopf-1 (Dkk-1) to drive Th2 and Th17 cell responses that correlated with reduced lung fungal burdens. Platelets simultaneously precluded lethal pulmonary hemorrhage resulting from fungal lung invasion. Thus, in addition to hemostasis, platelets promoted protection against C. albicans airway mycosis through an antifungal pathway involving candidalysin, GP1bα, and Dkk-1 that promotes Th2 and Th17 responses.
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Affiliation(s)
- Yifan Wu
- Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Zhimin Zeng
- Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Yubiao Guo
- Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Lizhen Song
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Jill E Weatherhead
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; The National School of Tropical Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Xinyan Huang
- Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yuying Zeng
- Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Lynn Bimler
- Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; The National School of Tropical Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Cheng-Yen Chang
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; The Translational Biology and Molecular Medicine Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - John M Knight
- Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; The Biology of Inflammation Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Christian Valladolid
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular Physiology & Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston Texas, 77030, USA
| | - Hua Sun
- Department of Otolaryngology, McGovern Medical School of the University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Miguel A Cruz
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston Texas, 77030, USA
| | - Bernhard Hube
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute Jena (HKI), Jena 07745, Germany; Institute of Microbiology, Friedrich Schiller University, Jena 07737, Germany
| | - Julian R Naglik
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 1UL, UK
| | - Amber U Luong
- Department of Otolaryngology, McGovern Medical School of the University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Farrah Kheradmand
- Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; The Biology of Inflammation Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston Texas, 77030, USA
| | - David B Corry
- Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; The Biology of Inflammation Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston Texas, 77030, USA.
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Jeong J, Lee HK. The Role of CD4 + T Cells and Microbiota in the Pathogenesis of Asthma. Int J Mol Sci 2021; 22:11822. [PMID: 34769255 PMCID: PMC8584410 DOI: 10.3390/ijms222111822] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/26/2021] [Accepted: 10/29/2021] [Indexed: 12/22/2022] Open
Abstract
Asthma, a chronic respiratory disease involving variable airflow limitations, exhibits two phenotypes: eosinophilic and neutrophilic. The asthma phenotype must be considered because the prognosis and drug responsiveness of eosinophilic and neutrophilic asthma differ. CD4+ T cells are the main determinant of asthma phenotype. Th2, Th9 and Tfh cells mediate the development of eosinophilic asthma, whereas Th1 and Th17 cells mediate the development of neutrophilic asthma. Elucidating the biological roles of CD4+ T cells is thus essential for developing effective asthma treatments and predicting a patient's prognosis. Commensal bacteria also play a key role in the pathogenesis of asthma. Beneficial bacteria within the host act to suppress asthma, whereas harmful bacteria exacerbate asthma. Recent literature indicates that imbalances between beneficial and harmful bacteria affect the differentiation of CD4+ T cells, leading to the development of asthma. Correcting bacterial imbalances using probiotics reportedly improves asthma symptoms. In this review, we investigate the effects of crosstalk between the microbiota and CD4+ T cells on the development of asthma.
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Affiliation(s)
| | - Heung Kyu Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea;
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Min HK, Kim S, Lee JY, Kim KW, Lee SH, Kim HR. IL-18 binding protein suppresses IL-17-induced osteoclastogenesis and rectifies type 17 helper T cell / regulatory T cell imbalance in rheumatoid arthritis. J Transl Med 2021; 19:392. [PMID: 34530864 PMCID: PMC8444577 DOI: 10.1186/s12967-021-03071-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 09/07/2021] [Indexed: 11/25/2022] Open
Abstract
Background Patients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteoarthritis (OA) or in healthy controls. In this study, we evaluated the effects of IL-18BP on osteoclastogenesis and T cell differentiation in RA in vitro. Methods Serum and SF of patients with RA and OA were collected to compare IL-18 and IL-18BP levels by the enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMCs) and SF mononuclear cells (SFMCs) of RA patients were cultured under type 17 helper T cell (Th17) polarisation conditions with or without IL-18BP. In addition, PBMCs were cultured in the presence of receptor activator of nuclear factor kappa-Β ligand (RANKL) or IL-17A with or without IL-18BP, and tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative polymerase chain reaction for expression levels of osteoclast-related genes were performed. Results IL-18 levels were higher in the serum and SF of patients with RA, whereas IL-18BP was lower in the SF of patients with RA than in the control group. Treatment of patients’ PBMCs with IL-18BP decreased the differentiation of CD4+ IL-17A+ and CD4+ RANKL+ T cells, whereas the differentiation of CD4+CD25highFOXP3+ T cell population increased in a dose-dependent manner. These changes in CD4+ T cell differentiation were also observed in the SFMCs of patients with RA. The levels IL-17A and soluble RANKL in the culture medium were significantly decreased by IL-18BP. IL-18BP administration decreased TRAP+ cell counts in a dose-dependent manner on the background of stimulation with RANKL-and IL-17A. In addition, expression levels of TRAP, NFATC1, CTSK, and TNFRSF11A (RANK) genes were lower in the IL-18BP treated cells. Conclusion We showed that IL-18BP can rectify the Th17/Treg imbalance and decrease IL-17-induced osteoclastogenesis in PBMCs from patients with RA. Therefore, IL-18BP may have therapeutic potential for RA treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-03071-2.
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Affiliation(s)
- Hong Ki Min
- Division of Rheumatology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, 05030, Republic of Korea
| | - Sehee Kim
- Division of Rheumatology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, 05030, Republic of Korea
| | - Ji-Yeon Lee
- The Rheumatism Research Center, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, 05030, Republic of Korea
| | | | - Sang-Heon Lee
- Division of Rheumatology, Department of Internal Medicine, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, 05030, Republic of Korea
| | - Hae-Rim Kim
- Division of Rheumatology, Department of Internal Medicine, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, 05030, Republic of Korea. .,Department of Rheumatology, Konkuk University Medical Center, 120-1 Neungdong-ro (Hwayang-dong), Gwangjin-gu, Seoul, 143-729, Republic of Korea.
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Hofmann MA, Fluhr JW, Ruwwe‐Glösenkamp C, Stevanovic K, Bergmann K, Zuberbier T. Role of IL-17 in atopy-A systematic review. Clin Transl Allergy 2021; 11:e12047. [PMID: 34429872 PMCID: PMC8361814 DOI: 10.1002/clt2.12047] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/25/2021] [Accepted: 06/25/2021] [Indexed: 02/05/2023] Open
Abstract
PURPOSE OF REVIEW Atopy is defined as the genetic predisposition to react with type I allergic diseases such as food-, skin-, and respiratory allergies. Distinct molecular mechanisms have been described, including the known Th2 driven immune response. IL-17A (IL-17) is mainly produced by Th17 cells and belongs to the IL-17 family of cytokines, IL-17A to F. While IL-17 plays a major role in inflammatory and autoimmune disorders, more data was published in recent years elucidating the role of IL-17 in allergic diseases. The present study aimed to elaborate specifically the role of IL-17 in atopy. METHODS A systematic literature search was conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials, regarding IL-17 and atopy/allergic diseases. RESULTS In total, 31 novel publications could be identified (food allergy n = 3, allergic asthma n = 7, allergic rhinitis [AR] n = 10, atopic dermatitis [AD] n = 11). In all allergic diseases, the IL-17 pathway has been investigated. Serum IL-17 was elevated in all allergic diseases. In AR, serum and nasal IL-17 levels correlated with the severity of the disease. In food allergies, serum IL-17E was also elevated in children. In AD, there is a trend for higher IL-17 values in the serum and skin specimen, while it is more expressed in acute lesions. In allergic asthma, serum IL-17 levels were increased. In two studies, higher serum IL-17 levels were found in severe persistent asthmatic patients than in intermittent asthmatics or healthy controls. Only one therapeutic clinical study exists on allergic diseases (asthma patients) using a monoclonal antibody against the IL-17 receptor A. No clinical efficacy was found in the total study population, except for a subgroup of patients with (post-bronchodilator) high reversibility. SUMMARY The role of IL 17 in the pathogenesis of allergic diseases is evident, but the involvement of the Th17 cytokine in the pathophysiological pathway is not conclusively defined. IL-17 is most likely relevant and will be a clinical target in subgroups of patients. The current data indicates that IL-17 is elevated more often in acute and severe forms of allergic diseases.
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Affiliation(s)
- Maja A. Hofmann
- Department of Dermatology and AllergyCharité ‐ Universitätsmedizin BerlinBerlinGermany
| | - Joachim W. Fluhr
- Department of Dermatology and AllergyCharité ‐ Universitätsmedizin BerlinBerlinGermany
| | | | - Katarina Stevanovic
- Department of Dermatology and AllergyCharité ‐ Universitätsmedizin BerlinBerlinGermany
| | | | - Torsten Zuberbier
- Department of Dermatology and AllergyCharité ‐ Universitätsmedizin BerlinBerlinGermany
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Fennen M, Weinhage T, Kracke V, Intemann J, Varga G, Wehmeyer C, Foell D, Korb-Pap A, Pap T, Dankbar B. A myostatin-CCL20-CCR6 axis regulates Th17 cell recruitment to inflamed joints in experimental arthritis. Sci Rep 2021; 11:14145. [PMID: 34239010 PMCID: PMC8266846 DOI: 10.1038/s41598-021-93599-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/23/2021] [Indexed: 01/02/2023] Open
Abstract
The interactions of fibroblast-like synoviocyte (FLS)-derived pro-inflammatory cytokines/chemokines and immune cells support the recruitment and activation of inflammatory cells in RA. Here, we show for the first time that the classical myokine myostatin (GDF-8) is involved in the recruitment of Th17 cells to inflammatory sites thereby regulating joint inflammation in a mouse model of TNFalpha-mediated chronic arthritis. Mechanistically, myostatin-deficiency leads to decreased levels of the chemokine CCL20 which is associated with less infiltration of Th17 cells into the inflamed joints. In vitro, myostatin alone or in combination with IL-17A enhances the secretion of CCL20 by FLS whereas myostatin-deficiency reduces CCL20 secretion, associated with an altered transmigration of Th17 cells. Thus, the communication between activated FLS and Th17 cells through myostatin and IL-17A may likely contribute to a vicious cycle of inflammation, accounting for the persistence of joint inflammation in chronic arthritis. Blockade of the CCL20–CCR6 axis by inhibition of myostatin may, therefore, be a promising treatment option for chronic inflammatory diseases such as arthritis.
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Affiliation(s)
- Michelle Fennen
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, 48149, Muenster, Germany
| | - Toni Weinhage
- Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster, Germany
| | - Vanessa Kracke
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, 48149, Muenster, Germany
| | - Johanna Intemann
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, 48149, Muenster, Germany
| | - Georg Varga
- Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster, Germany
| | - Corinna Wehmeyer
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, 48149, Muenster, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster, Germany
| | - Adelheid Korb-Pap
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, 48149, Muenster, Germany
| | - Thomas Pap
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, 48149, Muenster, Germany
| | - Berno Dankbar
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, 48149, Muenster, Germany.
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45
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Niu Y, Ye L, Peng W, Wang Z, Wei X, Wang X, Li Y, Zhang S, Xiang X, Zhou Q. IL-26 promotes the pathogenesis of malignant pleural effusion by enhancing CD4 + IL-22 + T-cell differentiation and inhibiting CD8 + T-cell cytotoxicity. J Leukoc Biol 2021; 110:39-52. [PMID: 33847412 DOI: 10.1002/jlb.1ma0221-479rr] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 02/05/2021] [Accepted: 03/03/2021] [Indexed: 01/21/2023] Open
Abstract
IL-26 is a newly discovered IL-10 cytokine family member mainly secreted by Th17 cells. However, the relationship between IL-26 and lung cancer remains unclear. The present study reported that IL-26 is involved in the production and promotion of malignant pleural effusion (MPE) for the first time. The concentrations of IL-26 and several Th17-related cytokines in MPE and peripheral blood (PB) from MPE patients were measured. IL-26, IL-10, and IL-6 were elevated in MPE compared to PB. The cell resource of IL-26 was primary Th17 cells measured by flow cytometry, whereas Tc17 cells and macrophages could also contribute to higher concentration of IL-26 in MPE. Abundant IL-6 and IL-23 in MPE could promote the frequency of IL-26 expressed by CD4+ T cells through phosphorylating STAT3 signaling pathway and promoting the expression of a specific Th17 lineage marker RORγt subsequently. IL-26 could selectively increase Th22 proportion through up-regulating the percentage of Ki-67 expressed by CD4+ T cells and the expression of IL-22 secreted by memory CD4+ T cells. In addition, IL-26 could decrease secretion of granzyme B. The tumor-killing activity of CD8+ T cells were inhibited as well when cocultured with malignant cells. Furthermore, the accumulation of IL-26 protein in MPE predicted poor patient survival. In summary, our results indicated that IL-26 was involved in the pathogenesis of MPE by exerting its impacts on both CD4+ T cells and CD8+ T cells.
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Affiliation(s)
- Yiran Niu
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Linlin Ye
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenbei Peng
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zihao Wang
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoshan Wei
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xu Wang
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yu Li
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Siyu Zhang
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xuan Xiang
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qiong Zhou
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Tu J, Huang W, Zhang W, Mei J, Zhu C. A Tale of Two Immune Cells in Rheumatoid Arthritis: The Crosstalk Between Macrophages and T Cells in the Synovium. Front Immunol 2021; 12:655477. [PMID: 34220809 PMCID: PMC8248486 DOI: 10.3389/fimmu.2021.655477] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/01/2021] [Indexed: 11/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Joint inflammation of RA is closely related to infiltration of immune cells, synovium hyperplasia, and superfluous secretion of proinflammatory cytokines, which lead to cartilage degradation and bone erosion. The joint synovium of RA patients contains a variety of immune cellular types, among which monocytes/macrophages and T cells are two essential cellular components. Monocytes/macrophages can recruit and promote the differentiation of T cells into inflammatory phenotypes in RA synovium. Similarly, different subtypes of T cells can recruit monocytes/macrophages and promote osteoblast differentiation and production of inflammatory cytokines. In this review, we will discuss how T cell-monocyte/macrophage interactions promote the development of RA, which will provide new perspectives on RA pathogenesis and the development of targeted therapy.
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Affiliation(s)
- Jiajie Tu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China
- Department of Gynecology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Wei Huang
- Department of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Weiwei Zhang
- Departments of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jiawei Mei
- Department of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Chen Zhu
- Department of Orthopaedics, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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47
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Zwain A, Aldiwani M, Taqi H. The Association Between Psoriasis and Cardiovascular Diseases. Eur Cardiol 2021; 16:e19. [PMID: 34040653 PMCID: PMC8145074 DOI: 10.15420/ecr.2020.15.r2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 02/16/2021] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular diseases and psoriasis have been well established as separate entities, however, there is uncertainty with regards to a link between the two diseases. A few environmental, psychological and social factors have been implicated as potential common risk factors that may exacerbate the two diseases, and an array of complex immune and non-immune inflammatory mediators can potentially explain a plausible link. Pharmacotherapy has also played a role in establishing a potential association, especially with the advent of biological agents which directly act on inflammatory factors shared by the two diseases. This review will look at existing evidence and ascertain a potential correlation between the two.
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Affiliation(s)
- Ahmed Zwain
- North West Deanery, Aintree University Hospital Liverpool, UK
| | - Mohanad Aldiwani
- East Midlands Deanery, University Hospitals of Leicester NHS Trust Leicester, UK
| | - Hussein Taqi
- East Midlands Deanery, Royal Derby Hospital Derby, UK
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48
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Akiyama S, Sakuraba A. Distinct roles of interleukin-17 and T helper 17 cells among autoimmune diseases. J Transl Autoimmun 2021; 4:100104. [PMID: 34179741 PMCID: PMC8188045 DOI: 10.1016/j.jtauto.2021.100104] [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: 05/08/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Interleukin (IL)-17 and T helper 17 (TH17) cells, a distinct subset of CD4+ T cells which promotes the expression of IL-17, mediate host defensive mechanisms to various infections and are involved in the pathogenesis of autoimmune diseases including inflammatory bowel disease (IBD), psoriasis, and rheumatic diseases. IL-17 inhibitors have shown to be effective in psoriasis, but failed to demonstrate response in IBD. Further, clinical trials of IL-17 inhibitors reported some cases of new onset IBD. We aim to discuss the roles of IL-17 and TH17 cells among autoimmune diseases and the possible immunological mechanisms of new onset IBD in patients undergoing IL-17 inhibitors. METHODS A non-systematic literature review using PubMed/Medline. RESULTS IL-17 inhibitors, which either target IL-17 A (secukinumab and ixekizumab) or the IL-17 receptor (brodalumab), have demonstrated clinical benefits in plaque psoriasis, psoriatic arthritis, or axial spondyloarthritis. However, secukinumab and brodalumab have shown no clinical benefit in Crohn's disease and led to frequent serious adverse events including worsening of Crohn's disease. Further, some cases of new onset IBD were reported in clinical trials of IL-17 inhibitors. Consistently, an animal model of colitis has demonstrated that IL-17 can directly inhibit the development of T helper 1 (TH1) cells and TH1 cells can induce aggressive colitis in the absence of IL-17 signaling. CONCLUSIONS IL-17 and TH17 cells might have protective rather than pro-inflammatory roles in the intestine. IL-17 inhibition may induce inflammation in the intestine by favoring TH1 pathways, which explain the lack of response to IL-17 inhibitors in IBD.
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Affiliation(s)
- Shintaro Akiyama
- Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, IL, USA
| | - Atsushi Sakuraba
- Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, IL, USA
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49
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Devenish LP, Mhlanga MM, Negishi Y. Immune Regulation in Time and Space: The Role of Local- and Long-Range Genomic Interactions in Regulating Immune Responses. Front Immunol 2021; 12:662565. [PMID: 34046034 PMCID: PMC8144502 DOI: 10.3389/fimmu.2021.662565] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/26/2021] [Indexed: 12/27/2022] Open
Abstract
Mammals face and overcome an onslaught of endogenous and exogenous challenges in order to survive. Typical immune cells and barrier cells, such as epithelia, must respond rapidly and effectively to encountered pathogens and aberrant cells to prevent invasion and eliminate pathogenic species before they become overgrown and cause harm. On the other hand, inappropriate initiation and failed termination of immune cell effector function in the absence of pathogens or aberrant tissue gives rise to a number of chronic, auto-immune, and neoplastic diseases. Therefore, the fine control of immune effector functions to provide for a rapid, robust response to challenge is essential. Importantly, immune cells are heterogeneous due to various factors relating to cytokine exposure and cell-cell interaction. For instance, tissue-resident macrophages and T cells are phenotypically, transcriptionally, and functionally distinct from their circulating counterparts. Indeed, even the same cell types in the same environment show distinct transcription patterns at the single cell level due to cellular noise, despite being robust in concert. Additionally, immune cells must remain quiescent in a naive state to avoid autoimmunity or chronic inflammatory states but must respond robustly upon activation regardless of their microenvironment or cellular noise. In recent years, accruing evidence from next-generation sequencing, chromatin capture techniques, and high-resolution imaging has shown that local- and long-range genome architecture plays an important role in coordinating rapid and robust transcriptional responses. Here, we discuss the local- and long-range genome architecture of immune cells and the resultant changes upon pathogen or antigen exposure. Furthermore, we argue that genome structures contribute functionally to rapid and robust responses under noisy and distinct cellular environments and propose a model to explain this phenomenon.
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Affiliation(s)
- Liam P Devenish
- Division of Chemical, Systems, and Synthetic Biology, Department of Integrative Biomedical Sciences, Institute of Infectious Disease & Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Musa M Mhlanga
- Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands.,Epigenomics & Single Cell Biophysics Group, Department of Cell Biology, Radboud University, Nijmegen, Netherlands.,Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Yutaka Negishi
- Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands.,Epigenomics & Single Cell Biophysics Group, Department of Cell Biology, Radboud University, Nijmegen, Netherlands.,Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
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50
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Carvalho AL, Hedrich CM. The Molecular Pathophysiology of Psoriatic Arthritis-The Complex Interplay Between Genetic Predisposition, Epigenetics Factors, and the Microbiome. Front Mol Biosci 2021; 8:662047. [PMID: 33869291 PMCID: PMC8047476 DOI: 10.3389/fmolb.2021.662047] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 03/04/2021] [Indexed: 12/13/2022] Open
Abstract
Psoriasis is a symmetric autoimmune/inflammatory disease that primarily affects the skin. In a significant proportion of cases, it is accompanied by arthritis that can affect any joint, the spine, and/or include enthesitis. Psoriasis and psoriatic arthritis are multifactor disorders characterized by aberrant immune responses in genetically susceptible individuals in the presence of additional (environmental) factors, including changes in microbiota and/or epigenetic marks. Epigenetic changes can be heritable or acquired (e.g., through changes in diet/microbiota or as a response to therapeutics) and, together with genetic factors, contribute to disease expression. In psoriasis, epigenetic alterations are mainly related to cell proliferation, cytokine signaling and microbial tolerance. Understanding the complex interplay between heritable and acquired pathomechanistic factors contributing to the development and maintenance of psoriasis is crucial for the identification and validation of diagnostic and predictive biomarkers, and the introduction of individualized effective and tolerable new treatments. This review summarizes the current understanding of immune activation, genetic, and environmental factors that contribute to the pathogenesis of psoriatic arthritis. Particular focus is on the interactions between these factors to propose a multifactorial disease model.
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Affiliation(s)
- Ana L Carvalho
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Christian M Hedrich
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.,Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, United Kingdom
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