WISP-3 facilitates CCL4-dependent monocyte migration and M1 polarization in rheumatoid arthritis by inhibiting miR-6894-5p

Chronic systemic inflammation and autoimmunity are hallmarks of rheumatoid arthritis (RA), an inflammatory illness that progressively deteriorates joints, resulting in permanent disability. Monocyte adhesion and infiltration into synovial tissue are critical steps in RA progression. WISP-3 (referred to as CCN6) is a member of the CCN family and plays a role in regulating various developmental processes. However, the role of WISP-3 in monocyte adhesion and macrophage polarization in RA remains unknown. Our high-throughput cytokine array data indicate that WISP-3 induces CCL4 synthesis in RA synovial fibroblasts (RASFs), subsequently enhancing monocyte adhesion to the synovium. Result from the GEO database confirm that levels of WISP-3 and CCL4 are markedly higher in RA patients compared to healthy controls. We also elucidated a detailed mechanism by which WISP-3 increases CCL4 synthesis in RASFs and promotes monocyte adhesion to the synovium by reducing miR-6894-5p expression via the MEK and ERK pathways. Furthermore, WISP-3 augments M1 macrophage polarization in the RA microenvironment. Thus, the WISP-3/CCL4 axis may serve as a novel therapeutic goal for RA treatment.