Exploring the IL-21/IL-21R Signaling Pathway in Rheumatoid Arthritis: Implications for Synoviocyte Survival and Disease Progression

The persistent presence of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) contributes significantly to joint damage, yet the anti-apoptotic mechanisms involved are not well understood. This study investigates how the interleukin-21 (IL-21)/IL-21 receptor (IL-21R) pathway affects RA-FLS survival during endoplasmic reticulum stress (ERS). Clinical data, in vitro, and in vivo experiments were comprehensively used. RA patients with moderate-high disease activity and anti-CCP antibodies have high serum IL-21 levels. IL-21 enhances HFLS-RA cell survival and prevents apoptosis under ERS by upregulating IL-21R. It activates autophagy, shown by increased LC3II/I; ratio and p62 degradation, and inhibits ERS-mediated apoptosis by downregulating GRP78 and CHOP. Overexpressing IL-21R boosts autophagy and suppresses ERS. Transcriptome analysis identified USP18 as a key downstream effector of IL-21R. Silencing USP18 increased GSDMD expression and negated IL-21R's protective effects. In vivo, silencing IL-21R reduced joint inflammation and cartilage degradation in RA mouse models, reversing excessive autophagy and ERS marker expression in synovial tissue. This study elucidates, for the first time, the mechanism by which IL-21/IL-21R synergistically modulates the survival of RA-FLS through the "autophagy-ERS balance" and the USP18/GSDMD axis.