Premium
Attenuation of Rheumatoid Arthritis Through the Inhibition of Tumor Necrosis Factor–Induced Caspase 3/Gasdermin E–Mediated Pyroptosis
Author(s) -
Zhai Zeqing,
Yang Fangyuan,
Xu Wenchao,
Han Jiaochan,
Luo Guihu,
Li Yehao,
Zhuang Jian,
Jie Hongyu,
Li Xing,
Shi Xingliang,
Han Xinai,
Luo Xiaoqing,
Song Rui,
Chen Yonghong,
Liang Jianheng,
Wu Shufan,
He Yi,
Sun Erwei
Publication year - 2022
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41963
Subject(s) - pyroptosis , rheumatoid arthritis , tumor necrosis factor alpha , arthritis , pathogenesis , cancer research , medicine , immunology , inflammation , inflammasome
Objective To determine the role of gasdermin E (GSDME)–mediated pyroptosis in the pathogenesis and progression of rheumatoid arthritis (RA), and to explore the potential of GSDME as a therapeutic target in RA. Methods The expression and activation of caspase 3 and GSDME in the synovium, macrophages, and monocytes of RA patients were determined by immunohistochemistry, immunofluorescence, and Western blot analysis. The correlation of activated GSDME with RA disease activity was evaluated. The pyroptotic ability of monocytes from RA patients was tested, and the effect of tumor necrosis factor (TNF) on caspase 3/GSDME‐mediated pyroptosis of monocytes and macrophages was investigated. In addition, collagen‐induced arthritis (CIA) was induced in mice lacking Gsdme , and the incidence and severity of arthritis were assessed. Results Compared to cells from healthy controls, monocytes and synovial macrophages from RA patients showed increased expression of activated caspase 3, GSDME, and the N‐terminal fragment of GSDME (GSDME‐N). The expression of GSDME‐N in monocytes from RA patients correlated positively with disease activity. Monocytes from RA patients with higher GSDME levels were more susceptible to pyroptosis. Furthermore, TNF induced pyroptosis in monocytes and macrophages by activating the caspase 3/GSDME pathway. The use of a caspase 3 inhibitor and silencing of GSDME significantly blocked TNF‐induced pyroptosis. Gsdme deficiency effectively alleviated arthritis in a mouse model of CIA. Conclusion These results support the notion of a pathogenic role of GSDME in RA and provide an alternative mechanism for RA pathogenesis involving TNF, which activates GSDME‐mediated pyroptosis of monocytes and macrophages in RA. In addition, targeting GSDME might be a potential therapeutic approach for RA.