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

Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by systemic inflammation and symmetric polyarthritis, primarily affecting the joints. This condition results in joint pain, swelling, stiffness, and damage, severely impacting the quality of life of those affected. The mechanisms behind RA involve complex interactions between immune cells, inflammatory cytokines, and signaling pathways. Among the key contributors to the disease are interleukin-6 (IL-6) and the NLRP3 inflammasome in macrophages. IL-6 is a pro-inflammatory cytokine that plays a crucial role in regulating immune responses and inflammation, while the NLRP3 inflammasome is a protein complex that activates caspase-1 and drives the release of inflammatory cytokines like IL-1β, which further intensifies inflammation.This study aimed to examine the relationship between IL-6 and the NLRP3 inflammasome in RA. Using a collagen-induced arthritis (CIA) mouse model, which replicates many features of human RA, we found that inhibiting IL-6 resulted in a significant decrease in NLRP3 inflammasome activation. These results suggest that IL-6 is a critical regulator of inflammasome activity in the inflammatory environment of RA. To further elucidate the molecular mechanisms at play, we conducted in vitro experiments and demonstrated that IL-6 directly activates the NLRP3 inflammasome in macrophages, a process dependent on cathepsin B (CTSB) and ATP. This highlights a key signaling pathway through which IL-6 mediates inflammasome activation. Moreover, our findings revealed that S100A9, a damage-associated molecular pattern (DAMP) protein, is induced by ATP and serves as an important mediator in NLRP3 inflammasome activation. S100A9 facilitated the interaction between CTSB and NLRP3, promoting inflammasome formation and activation. This discovery of the IL-6-CTSB-S100A9-NLRP3 interaction represents a novel mechanism by which IL-6 drives inflammasome activation in RA. The identification of this IL-6–NLRP3 inflammasome signaling pathway provides a potential new target for RA therapies. Disrupting the interaction between IL-6 and the NLRP3 inflammasome could help reduce chronic inflammation and prevent joint damage associated with RA. These findings offer a deeper understanding of the CA-074 methyl ester molecular pathways involved in RA and could lead to the development of more targeted and effective treatments. Further research is needed to explore potential inhibitors or modulators of this pathway and assess their clinical potential in treating RA.