Leptin promotes plasma cell generation and exacerbates collagen-induced arthritis

Abstract

Abstract Plasma cells (PCs) contribute to the relapse of many autoimmune diseases, especially in patients with rheumatoid arthritis (RA) after rituximab treatment. Increasing evidence indicates a crucial role of leptin in autoimmune pathogenesis via enhancing CD4+ T cell responses, but whether and how leptin regulates PCs remain largely unclear. In collagen-induced arthritis (CIA) mice, we detected increased levels of leptin and anti-collagen II (CII) antibodies in the synovial fluid (SF) and sera of mice at acute and chronic stages of CIA. Higher percentage and cell number of plasma cells (PCs) were observed in the SF of CIA mice. Leptin receptor-deficient (db/db) mice exhibited ameliorated CIA development with reduced PCs responses and CII-specific antibody production. Intra-articular injection of recombinant leptin enhanced PCs responses and CII-specific antibody production and joint damage. Importantly, intra-articular injection of a soluble leptin blocker (ObR:Fc) deceased PCs responses, CII-specific antibody production and joint damage. Mechanistic studies revealed that leptin promoted CD138+IFR4+ PC generation from GL-7+Fas+ germinal center B cells via activating Akt-mTOR-IRF4 axis. Moreover, rapamycin treatment attenuated leptin-induced IRF4 expression and PCs generation. In RA patients, leptin levels and autoantibody production were positively correlated with disease activity (DAS28 score) with increased CD38+CD27+ plasmablasts detected in the synovium of active RA patients. Together, these findings demonstrated that leptin enhanced PCs responses via ObR-Akt-mTOR-IRF4 axis and exacerbated CIA development, indicating that leptin blockade may serve as a potential therapeutic target for the treatment of RA.