Attenuation of Rheumatoid Arthritis Through the Inhibition of Tumor Necrosis Factor–Induced Caspase 3/Gasdermin E–Mediated Pyroptosis

Abstract

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.

Gasdermin-E Mediated Pyroptosis—A Novel Mechanism Regulating Migration, Invasion and Release of Inflammatory Cytokines in Rheumatoid Arthritis Fibroblast-like Synoviocytes

“…A recent study also showed that GSDMD-mediated monocytes pyroptosis was involved in persistent inflammatory cytokine release in RA pathology ( Wu et al, 2020 ). The latest research ultimately studied the pathogenic role of GSDME in monocytes, macrophages and animal models of RA, suggesting that GSDME might be a potential therapeutic target for RA ( Zhai et al, 2021 ). However, involvement of GSDME-mediated pyroptosis in the function of RA-FLSs has not yet been reported.…”

“…Based on this feature, pyroptosis might play a crucial role in the genesis and development of RA. A study has implicated the importance of GSDMD-mediated monocytes pyroptosis in RA pathology ( Wu et al, 2020 ), and Ze-Qing Zhai’s latest article revealed a pathogenic role of GSDME in the pyroptosis of monocytes and macrophages in RA ( Zhai et al, 2021 ). However, the occurrence of pyroptosis as well as its mechanism and effect in RA-FLSs remain unknown.…”

Gasdermin E: A Prospective Target for Therapy of Diseases

“…Meanwhile, the increased trimethylamine-N-oxide in periodontitis patients damages peripheral endothelial progenitor cells through pyroptosis driven by Bax/caspase-3/GSDME pathway, suggesting that GSDME activation may also be associated with endothelial dysfunction in periodontitis patients ( Zhou et al, 2021 ). More recently, studies have certified that pyroptosis mediated by the caspase-3/GSDME axis is also concerned with inflammatory skin diseases ( Liu J. et al, 2021 ), idiopathic inflammatory myopathies ( Liu M. et al, 2020 ) and rheumatoid arthritis ( Zhai et al, 2022 ). These researches demonstrated that GSDME has been identified as a potential therapeutic target for inflammation.…”

No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death

“…On the other hand, GSDME-induced pyroptosis and the consequent inflammatory response contributes to H7N9 influenza-mediated lethality in mice [ 124 ]. Recent findings also correlate GSDME levels and activation in patient intestinal mucosa or synovial immune cells with Crohn's disease and rheumatoid arthritis severity, respectively, and mice deficient in GSDME were protected from chemical-induced (2,4,6-trinitrobenzenesulfonic acid) colitis or collagen-induced arthritis [ 125 , 126 ]. These studies highlight how an excess of GSDME-driven cell death can cause pathological inflammatory responses.…”