Polymorphonuclear Myeloid-Derived Suppressor Cells Promote Inflammation Progression of Rheumatoid Arthritis by Inducing Age-Associated B Cell Proliferation and Differentiation via the BAFF-Mediated SYK-ERK1/2 Pathway

Background In rheumatoid arthritis (RA), both polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and age-associated B cells (ABCs) are significantly elevated in affected joints and are closely linked to disease progression. However, their interaction remains poorly understood. This study aims to explore the regulatory role of PMN-MDSCs on ABCs and the underlying mechanisms, offering new insights into RA pathogenesis and potential therapeutic targets. Methods We conducted flow cytometry analysis to assess PMN-MDSCs and ABCs proportion and their correlation in collagen-induced arthritis (CIA) mice. We used RNA sequencing (RNA-seq) to characterize transcriptomic profiles of CD11c ⁺ B cells from CIA mice. In vitro studies examined T-bet expression in CD11c ⁺ B cells co-cultured with CIA-derived PMN-MDSCs. We assessed BAFF effects on ABCs proliferation and differentiation through flow cytometry and validated findings using anti-BAFF antibodies in PMN-MDSCs/CD11c ⁺ B cells co-cultures. We used western blot and flow cytometry analyses to identify BAFF-mediated signaling pathways in CD11c ⁺ B cells. In vivo study evaluated the therapeutic potential of pathway inhibitors in CIA mice. The ratio and regulatory correlation of PMN-MDSCs and ABCs were also assessed by flow cytometry in RA patients. Results Using a CIA mouse model, we observed increased populations of both PMN-MDSCs and ABCs in the joints and spleens, with a strong positive correlation in joint tissues. RNA sequencing of CIA-derived CD11c ⁺ B cells revealed distinct pro-inflammatory and chemotactic signatures. PMN-MDSCs enhanced T-bet expression in CD11c ⁺ B cells through non-contact-dependent mechanisms, driving ABCs differentiation. BAFF was found to support ABC proliferation and differentiation. Mechanistically, PMN-MDSCs-derived BAFF activated the SYK-ERK1/2 signaling pathway via BAFF receptor (BAFFr), upregulating T-bet expression in CD11c ⁺ B cells. In vivo, inhibition of SYK ameliorated arthritis symptoms and reduced ABC populations across tissues. Similarly, patients with RA exhibited elevated levels of PMN-MDSCs and ABCs in both blood and synovial fluid, with a significant correlation between the two. Additionally, RA-derived PMN-MDSCs promoted ABCs differentiation in vitro. Conclusion These findings highlight the role of PMN-MDSCs in driving RA inflammation by promoting ABC proliferation and differentiation via the BAFF-mediated SYK-ERK1/2 pathway.