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.

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An increase in apoptosis and/or defects in the clearance of apoptotic cells resulting in massive secondary necrosis have been recognized as the main causes of systemic lupus erythematosus (SLE). Recent findings have revealed that gasdermin E (GSDME)-mediated pyroptosis is a mechanism associated with secondary necrosis. We aimed to investigate the effects of GSDME-mediated pyroptosis on disease activity in lupus mice. In vivo, high levels of GSDME expression were observed in the renal tubules of pristane-induced lupus (PIL) mice and SLE patients. In lupus mice, GSDME knockout or SP600125 administration effectively ameliorated lupus-like features by inhibiting GSDME-mediated renal tubular epithelial cell pyroptosis. In vitro, treatment with tumour necrosis factor-α (TNF-α) plus cycloheximide (CHX) or SLE sera induced HK2 cells to undergo pyroptosis in a caspase-3- and GSDME-dependent manner. Likewise, SP600125 significantly reduced GSDME expression and decreased pyroptosis in HK2 cells. GSDME-mediated pyroptosis may be associated with SLE pathogenesis, and targeting GSDME may be a potential strategy for treating SLE.

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Background:Increased apoptosis and/or defect in clearance apoptotic cells resulting in massive secondary necrosis have been recognized as the main causes of systemic lupus erythematosus. Recent findings have revealed that GSDME, a membrane pore protein downstream of caspase-3, is a key mediator of secondary pyroptosis and cellular membrane disruption. Here, we aim to investigate the effects of secondary pyroptosis on disease activity in lupus mice. Methods:In vivo, Pristane-induced lupus mice were treated with JNK inhibitor SP600125 or vehicle. The disease severity was evaluated and the expression of GSDME and cleaved-caspase-3 detected. In vitro, HK2 human tubular epithelial cells were pretreated with SP600125, followed by treatment with apoptosis inducer, TNF+CHX, or SLE sera. And then the secondary pyroptosis were examined. Results:In vivo, high levels of GSDME expression were revealed in renal tubules in PIL mice and SLE patients. In lupus mice, SP600125 administration effectively ameliorated lupus-like features and importantly, reduced the expression of GSDME and cleaved caspase-3 in renal tubules. In vitro, treatment with TNF+CHX or SLE sera induced HK2 cells to undergo secondary pyroptosis in a caspase-3-GSDME dependent manner. Likewise, SP600125 significantly reduced GSDME expression and decreased the secondary pyroptosis in HK2 cells. Conclusions:The GSDME-mediated pyroptosis may be one of the pathogenesis of SLE and targeting GSDME may be a potential strategy for treating SLE.