IL-6 promotes collagen-induced arthritis by activating the NLRP3 inflammasome through the cathepsin B/S100A9-mediated pathway

Rheumatoid arthritis (RA) is an inflammatory disease with symmetric polyarthritis. IL-6 and NLRP3 inflammasome in macrophages contribute to the pathogenesis of RA. This study aimed to investigate the relationship between IL-6 and the NLRP3 inflammasome in RA. Here, we found that IL-6 inhibition reduced NLRP3 inflammasome activation in mice with collage-induced arthritis (CIA). In vitro studies showed that IL-6 directly induced NLRP3 inflammasome activation via Cathepsin B (CTSB) in the presence of ATP. In addition, S100A9 induced by ATP stimulation promoted the interaction of CTSB and NLRP3 to activate the NLRP3 inflammasome. Our findings show a novel mechanism of NLRP3 inflammasome activation by IL-6 that may lead to a potential therapy for RA by interrupting the interaction between IL-6 and the NLRP3 inflammasome.