Polymorphonuclear Myeloid‐Derived Suppressor Cells Promote Rheumatoid Arthritis by Inducing Age‐Associated B Cells Proliferation and Differentiation via the <scp>BAFF</scp> ‐Mediated <scp>SYK</scp> ‐ <scp>ERK1</scp> /2 Pathway

ABSTRACT In rheumatoid arthritis (RA), there is a marked elevation of both polymorphonuclear myeloid‐derived suppressor cells (PMN‐MDSCs) and age‐associated B cells (ABCs) within affected joints, which are closely associated with the progression of disease. However, the interactions between these cell types remain poorly understood. This study seeks to elucidate the regulatory influence of PMN‐MDSCs on ABCs and to uncover the underlying mechanisms, thereby providing novel insights into the pathogenesis of RA and identifying potential therapeutic targets. We observed increased frequencies of both PMN‐MDSCs and ABCs in the joints and spleens of collagen‐induced arthritis (CIA) mouse model, with a strong positive correlation specifically in joint tissues. RNA sequencing of CD11c + B cells derived from CIA mice revealed distinct pro‐inflammatory and chemotactic profiles. In vitro, PMN‐MDSCs enhanced T‐bet expression in CD11c + B cells and drove ABCs differentiation, independent of direct cell contact. B‐cell activating factor (BAFF) was found to support ABCs proliferation and differentiation. Mechanistically, BAFF derived from PMN‐MDSCs activated the SYK‐ERK1/2 signaling pathway via the BAFF receptor (BAFFr), leading to upregulation of T‐bet expression in CD11c + B cells. SYK inhibitor ameliorated arthritis symptoms and reduced ABCs populations across tissues. And patients with RA exhibited increased PMN‐MDSCs and ABCs in both blood and synovial fluid (SF), with a significant correlation between the two cell types. Furthermore, PMN‐MDSCs derived from RA patients facilitated the differentiation of ABCs in vitro. These findings highlight the role of PMN‐MDSCs in driving RA inflammation by promoting the proliferation and differentiation of ABCs through the BAFF‐mediated SYK‐ERK1/2 signaling pathway.