Sijie Fang1,2,3,4, Yazhuo Huang1,2,3,4, Xingtong Liu1,2, Sisi Zhong1,2, Ningjian Wang5, Binbin Zhao3,4,6, Yinwei Li1,2, Jing Sun1,2, Yang Wang1,2, Shuo Zhang1,2, Ping Gu1,2, Huifang Zhou1,2, Bin Li2,3,4, Xianqun Fan1,2. 1. Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. 2. Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. 3. Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China. 4. Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai, China. 5. Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. 6. CAS Center for Excellence in Molecular Cell Science, CAS Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Abstract
Purpose: Recent reports suggest that Th17 immunity and bone marrow-derived CD34+ fibrocytes contribute to the pathogenesis of Graves' orbitopathy (GO). This study investigated interactions between Th17 cells and fibrocytes in GO inflammation in Chinese subjects. Methods: Th17 cells and fibrocytes were derived from blood samples from Chinese GO patients and healthy controls. Proportions and phenotypes of Th17 cells, regulatory T cells (Tregs), and fibrocytes were examined by flow cytometry. Exogenous IL-17A was used to study inflammatory activity of fibrocytes from GO patients and control subjects. Coculture, quantitative RT-PCR, Luminex, and transwell assays were performed to investigate the relationship between Th17 cells and fibrocytes. Results: CC-chemokine receptor 6 (CCR6+) Th17 cells were increased in both active (P < 0.001) and inactive (P < 0.05) GO patients, compared with healthy controls. There was a positive correlation between number of CCR6+ Th17 cells and GO clinical activity score (P < 0.0001, r = 0.8176). Further, CD34+ fibrocytes were increased in GO patients, with increased expression of IL-17RA (P < 0.05), CD80 (P < 0.05), and CD86 (P < 0.05). A decreased population of effector Treg cells (P < 0.01) and increased CTLA-4 expression on naïve Treg cells (P < 0.05) were observed in GO patients. IL-17A stimulated cytokine production in fibrocytes; GO fibrocytes exhibited more robust production than normal fibrocytes. Autologous Th17 cells promoted inflammatory and antigen-presenting functions of GO fibrocytes; conversely, fibrocytes enhanced Th17 cell-function and recruited Th17 cells in a macrophage inflammatory protein 3 (MIP-3)/CCR6-dependent manner. Conclusions: The crosstalk between CCR6+ Th17 cells and fibrocytes plays a role in the pathogenesis of GO. Suppressing these interactions may be a candidate molecular target for therapeutic approaches of GO.
Purpose: Recent reports suggest that Th17 immunity and bone marrow-derived CD34+ fibrocytes contribute to the pathogenesis of Graves' orbitopathy (GO). This study investigated interactions between Th17 cells and fibrocytes in GO inflammation in Chinese subjects. Methods: Th17 cells and fibrocytes were derived from blood samples from Chinese GO patients and healthy controls. Proportions and phenotypes of Th17 cells, regulatory T cells (Tregs), and fibrocytes were examined by flow cytometry. Exogenous IL-17A was used to study inflammatory activity of fibrocytes from GO patients and control subjects. Coculture, quantitative RT-PCR, Luminex, and transwell assays were performed to investigate the relationship between Th17 cells and fibrocytes. Results:CC-chemokine receptor 6 (CCR6+) Th17 cells were increased in both active (P < 0.001) and inactive (P < 0.05) GO patients, compared with healthy controls. There was a positive correlation between number of CCR6+ Th17 cells and GO clinical activity score (P < 0.0001, r = 0.8176). Further, CD34+ fibrocytes were increased in GO patients, with increased expression of IL-17RA (P < 0.05), CD80 (P < 0.05), and CD86 (P < 0.05). A decreased population of effector Treg cells (P < 0.01) and increased CTLA-4 expression on naïve Treg cells (P < 0.05) were observed in GO patients. IL-17A stimulated cytokine production in fibrocytes; GO fibrocytes exhibited more robust production than normal fibrocytes. Autologous Th17 cells promoted inflammatory and antigen-presenting functions of GO fibrocytes; conversely, fibrocytes enhanced Th17 cell-function and recruited Th17 cells in a macrophage inflammatory protein 3 (MIP-3)/CCR6-dependent manner. Conclusions: The crosstalk between CCR6+ Th17 cells and fibrocytes plays a role in the pathogenesis of GO. Suppressing these interactions may be a candidate molecular target for therapeutic approaches of GO.
Authors: Harkaran S Rana; Sruti S Akella; Carson E Clabeaux; Zachary P Skurski; Vinay K Aakalu Journal: Ocul Surf Date: 2022-02-12 Impact factor: 6.268