PMN-MDSCS PROMOTE ABCS TO AGGRAVATE RHEUMATOID ARTHRITIS INFLAMMATION

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. Using a collagen-induced arthritis (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. In vitro, PMN-MDSCs enhanced T-bet expression in CD11c+ B cells through non-contact-dependent mechanisms, driving ABC differentiation. B-cell activating factor (BAFF) was found to support ABC proliferation and differentiation. Mechanistically, PMN-MDSCs-derived BAFF activated the SYK-ERK1/2 signaling pathway via the BAFF receptor (BAFFr), thereby 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 ABC differentiation in vitro. 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.