Extracellular cyclophilin a binding to CD146 is critical for Th17 cell differentiation in rheumatoid arthritis.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint synovial inflammation. Despite advancements in therapeutic strategies, the critical underlying mechanisms driving RA progression remain incompletely understood, and there is an ongoing need for novel therapeutic targets. We observed that high-level expression of extracellular cyclophilin A (eCypA) in patients with RA was associated with increased disease severity. Anti-CypA monoclonal antibody (mAb) treatment alleviated arthritis in both collagen-induced and collagen antibody-induced arthritis mouse models, outperforming anti-TNF-α mAb therapy. Single-cell RNA sequencing revealed that the anti-CypA mAb inhibited STAT3-mediated Th17 cell differentiation. Mechanistically, the binding of eCypA to the cell-surface receptor CD146 on CD4T cells promoted STAT3-mediated Th17 cell differentiation by increasing CD146 dimerization. Additionally, conditional CD146 knockout in CD4T cells suppressed Th17 cell differentiation and alleviated arthritis in a mouse model. In summary, our findings demonstrate that eCypA drives Th17 differentiation in RA by binding to CD146 and that blocking eCypA binding to CD146 is a promising strategy for RA treatment.