To determine the role of gasdermin E (GSDME)-mediated pyroptosis in the pathogenesis and progression of rheumatoid arthritis (RA), and explore the potential therapeutic targets for RA.
The expression and activation of caspase3 and GSDME in the synovium, macrophages, and monocytes of RA patients was detected 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 also tested. In addition, the effect of TNF-α on caspase3/GSDME-mediated pyroptosis of monocytes and macrophages was investigated. Furthermore, mice lacking Gsdme were subjected to collagen-induced arthritis, and the incidence and severity of arthritis was assessed.
Monocytes and synovial macrophages from RA patients showed increased expression of activated caspase3, GSDME, and GSDME-N. The expression of GSDME-N in monocytes from RA patients correlated positively with the disease activity. Monocytes from RA patients with higher GSDME levels were more susceptible to pyroptosis. Furthermore, TNF-α induced pyroptosis in monocytes and macrophages by activating the caspase3/GSDME pathway. The use of a caspase3 inhibitor and silencing of GSDME significantly blocked TNF-α-induced pyroptosis. Gsdme deficiency effectively alleviated arthritis in a collagen-induced arthritis mice model.
These results support a pathogenic role of GSDME in RA and provide an alternative mechanism for RA pathogenesis involving TNF-α, which activates GSDME-mediated pyroptosis of monocytes and macrophages in RA. In addition, targeting GSDME might be a potential therapeutic approach for RA.