SYK Activation Enhances Dendritic Cell Functions in Spontaneous Rheumatoid Arthritis.

The pathogenesis of rheumatoid arthritis (RA) involves an aberrant number and/or activation of dendritic cells (DCs) within the synovial microenvironment. Targeting synovial DCs represents an attractive approach for the treatment of RA. Spleen tyrosine kinase (SYK), a pivotal molecule in immune cell receptor signaling pathways, is known to play a critical role in RA progression. However, the impact of SYK on DC biology under RA-specific pathological conditions remains incompletely understood. In this study, we employed a spontaneous RA mouse model carrying a gain-of-function SYK variant (SYK(S544Y)) to investigate the effects of SYK activation on DCs. Our findings demonstrate that SYK activation promotes the expansion of the DCs population (CD11C(+)MHCII(+)), particularly the CD11C(+)MHCII(+)CD11B(+)CD8a(−) subtype, in blood, spleen, and ankle. Furthermore, SYK activation enhances DC maturation and endocytosis by upregulating CD40 and CD86. Additionally, bone-marrow-derived DCs from SYK(S544Y) mice exhibit increased T-cell proliferative activity. Collectively, these results suggest that gain-of-function SYK may contribute to RA pathogenesis by promoting DC expansion and maturation, thereby modulating immune responses in the synovial environment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10753-025-02405-2.