Sijie Fang1, Yazhuo Huang1, Shuaiwei Wang1, Yidan Zhang1, Xuerui Luo1, Luyan Liu1, Sisi Zhong1, Xingtong Liu1, Dan Li1, Rui Liang1, Piccioni Miranda1, Ping Gu1, Huifang Zhou1, Xianqun Fan1, Bin Li1. 1. 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.
Abstract
CONTEXT: 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. OBJECTIVE: We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO. DESIGN/SETTING/PARTICIPANTS: Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects. MAIN OUTCOME MEASURES: Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed. RESULTS: 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. CONCLUSION: 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.
CONTEXT: 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. OBJECTIVE: We sought to investigate the pathogenic function of IL-17A-producing T cells in TAO. DESIGN/SETTING/PARTICIPANTS: Blood samples and orbital fibroblasts (OFs) were collected from TAO patients and healthy subjects. MAIN OUTCOME MEASURES: Flow cytometry, real-time PCR, cytokine-specific ELISA, and Western blotting were performed. RESULTS: 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. CONCLUSION: 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: Peter N Taylor; Lei Zhang; George J Kahaly; Marian Ludgate; Richard W J Lee; Ilaria Muller; Daniel G Ezra; Colin M Dayan Journal: Nat Rev Endocrinol Date: 2019-12-30 Impact factor: 43.330