Jiehua Wang1, Min Dai1, Yange Cui2, Guojun Hou2, Jun Deng1, Xin Gao1, Zhuojun Liao1, Ya Liu1, Yao Meng1, Lingling Wu1, Chao Yao2, Yan Wang2, Jie Qian1, Qiang Guo1, Huihua Ding1, Bo Qu1, Nan Shen3,4. 1. Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 2. Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. 3. Shanghai Institute of Rheumatology, and China-Australia Centre for Personalised Immunology, Renji Hospital, School of Medicine, and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. 4. Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Abstract
OBJECTIVE: Increasing evidence indicates that the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway has a critical pathogenic role in systemic lupus erythematosus (SLE). Expression levels of the interferon (IFN)-inducible gene IFIT3 are elevated in SLE patients. However, it is still not clear how IFIT3 contributes to the pathogenesis of SLE. This study was undertaken to investigate the activation of the cGAS/STING signaling pathway in human SLE monocytes, and to determine how elevated expression of IFIT3 could contribute to overactive cGAS/STING signaling in patients with SLE. METHODS: Monocytes from SLE patients or healthy controls were examined for activity of the cGAS/STING signaling pathway and expression levels of IFIT3. Correlations between cGAS/STING signaling activity and SLE clinical features were analyzed. Gain- or loss-of-function experiments were used to determine the role of IFIT3 in cGAS/STING signaling. Coimmunoprecipitation assays were used to identify the interaction between IFIT3 and other proteins. RESULTS: The cGAS/STING signaling pathway was found to have enhanced activity in monocytes from SLE patients compared to healthy controls, as indicated by the higher expression of IFNβ downstream. Levels of IFIT3 were significantly elevated in human SLE monocytes, and this was positively correlated with the activity of the cGAS/STING signaling pathway. In vitro, the expression of VACV70-induced IFNβ was reduced by knockdown of IFIT3, whereas overexpression of IFIT3 produced an opposite effect. Finally, IFIT3 was found to interact with both STING and TANK-binding kinase 1. CONCLUSION: These findings suggest that IFIT3 is one of the genes that contributes to the overactive cGAS/STING signaling pathway in human SLE monocytes. IFIT3 may therefore serve as a novel therapeutic target for blocking the production of type I IFN and other proinflammatory cytokines by the cGAS/STING signaling pathway in patients with SLE.
OBJECTIVE: Increasing evidence indicates that the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway has a critical pathogenic role in systemic lupus erythematosus (SLE). Expression levels of the interferon (IFN)-inducible gene IFIT3 are elevated in SLEpatients. However, it is still not clear how IFIT3 contributes to the pathogenesis of SLE. This study was undertaken to investigate the activation of the cGAS/STING signaling pathway in humanSLE monocytes, and to determine how elevated expression of IFIT3 could contribute to overactive cGAS/STING signaling in patients with SLE. METHODS: Monocytes from SLEpatients or healthy controls were examined for activity of the cGAS/STING signaling pathway and expression levels of IFIT3. Correlations between cGAS/STING signaling activity and SLE clinical features were analyzed. Gain- or loss-of-function experiments were used to determine the role of IFIT3 in cGAS/STING signaling. Coimmunoprecipitation assays were used to identify the interaction between IFIT3 and other proteins. RESULTS: The cGAS/STING signaling pathway was found to have enhanced activity in monocytes from SLEpatients compared to healthy controls, as indicated by the higher expression of IFNβ downstream. Levels of IFIT3 were significantly elevated in humanSLE monocytes, and this was positively correlated with the activity of the cGAS/STING signaling pathway. In vitro, the expression of VACV70-induced IFNβ was reduced by knockdown of IFIT3, whereas overexpression of IFIT3 produced an opposite effect. Finally, IFIT3 was found to interact with both STING and TANK-binding kinase 1. CONCLUSION: These findings suggest that IFIT3 is one of the genes that contributes to the overactive cGAS/STING signaling pathway in humanSLE monocytes. IFIT3 may therefore serve as a novel therapeutic target for blocking the production of type I IFN and other proinflammatory cytokines by the cGAS/STING signaling pathway in patients with SLE.
Authors: T Shimizu; H Nakamura; A Takatani; M Umeda; Y Horai; S Kurushima; T Michitsuji; Y Nakashima; A Kawakami Journal: Clin Exp Immunol Date: 2018-11-28 Impact factor: 4.330
Authors: Yang Li; Sharmy J James; David H Wyllie; Claire Wynne; Agnes Czibula; Ahmed Bukhari; Katherine Pye; Seri Musfirah Bte Mustafah; Roberta Fajka-Boja; Eniko Szabo; Adrienn Angyal; Zoltan Hegedus; Laszlo Kovacs; Adrian V S Hill; Caroline A Jefferies; Heather L Wilson; Zhang Yongliang; Endre Kiss-Toth Journal: Proc Natl Acad Sci U S A Date: 2019-07-25 Impact factor: 11.205
Authors: Xingwang Zhao; Longlong Zhang; Juan Wang; Min Zhang; Zhiqiang Song; Bing Ni; Yi You Journal: J Transl Med Date: 2021-01-19 Impact factor: 5.531