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

Introduction: 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).

Methods: Clinical data, in vitro, and in vivo experiments were comprehensively used.

Results: 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.

Discussion: 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.

Endoplasmic reticulum stress; IL-21/IL-21R pathway; USP18/GSDMD axis; fibroblast-like synoviocytes; rheumatoid arthritis.