Interleukin-6 in synovial fluid drives the conversion of DC2s to DC3s in inflammatory arthritis

Inflammatory arthritis (IA) is characterized by persistent joint inflammation and immune cell infiltration, including CD1c⁺ dendritic cells (DCs), comprising DC2s and DC3s. To investigate their developmental and functional specialization in IA, we characterized DC2s and DC3s in the peripheral blood (PB) and synovial fluid (SF) of patients with IA. DC3 frequencies were increased in PB of patients with juvenile idiopathic arthritis and correlated with disease activity in early rheumatoid arthritis. While PB DC3s showed strongly impaired T cell activation, SF DC3s induced only marginally lower T cell proliferation compared to DC2s and primed higher frequencies of IL-17⁺ and IFN $\gamma$ ⁺ T cells. Furthermore, SF from patients with IA induced the DC3 phenotype in DC2s from healthy donors, an effect abrogated by IL-6 receptor blockade and dependent on JAK/STAT3 signaling. Altogether, these findings reveal the impact of tocilizumab and JAK inhibitors on inflammatory DC3s in IA and offer mechanistic insights for IA treatment.