title: IL-17A Exacerbates Fibrosis by Promoting the Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO.
abstract: The development of thyroid-associated ophthalmopathy (TAO) is associated with self-immune dysfunction. Recent findings in TAO and Graves' disease indicate that IL-17A may also be involved in the autoimmunity of TAO.
  
  
  
  We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO.
  
  
  
  Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects.
  
  
  
  Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed.
  
  
  
  Here, we showed a significantly higher proportion of IL-17A-producing T cells in TAO patients and the recruitment of both CD4(+) and CD8(+) T cells in TAO orbits. TAO orbital tissues expressed more IL-17A receptor, IL-17A, and its related cytokines, with severe fibrotic change compared with normal controls. Furthermore, we validated that IL-17A could enhance the proinflammatory function of OFs and stimulate the production of extracellular matrix proteins in OFs but not eyelid fibroblasts. The mechanisms involved in this enhancement mainly relied on MAPK activation. Finally, we observed that the deubiquitinase inhibitor vialinin A could down-regulate retinoic acid receptor-related orphan receptor-γt expression and decrease IL-17A level in TAO patients.
  
  
  
  Our observations illustrate the potential pathogenic role of IL-17A-producing T cells in the inflammatory response and fibrosis of TAO. The effect of vialinin A on the reduction of retinoic acid receptor-related orphan receptor-γt level implicates its potential role as a novel therapeutic agent for TAO and other autoimmune disorders in the future.
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Sijie
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Yazhuo
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Shuaiwei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Yidan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Xuerui
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Luyan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Sisi
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Xingtong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Rui
authors.initials: R
authors.lastname: Liang
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Piccioni
authors.initials: P
authors.lastname: Miranda
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Ping
authors.initials: P
authors.lastname: Gu
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Huifang
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Xianqun
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Ophthalmology (S.F., Y.H., Y.Z., S.Z., X.Li., P.G., H.Z., X.F.), Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011; and Key Laboratory of Molecular Virology and Immunology (S.F., S.W., X.Lu., L.L., D.L., R.L., P.M., B.L.), Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences Medical School, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced; D049970:Graves Ophthalmopathy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism / Q000494:pharmacology*; D009915:Orbit / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014801:Vitamin A / Q000494:pharmacology
chemical_list: C508717:IL17A protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D014801:Vitamin A