Blockade of KCa3.1 ameliorates rheumatoid arthritis by suppressing macrophage M1 polarization via the NLRP3 inflammasome signaling pathway.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and joint destruction, yet current therapies often fail to fully restore immune balance. This study identifies the calcium-activated potassium channel KCa3.1 (KCNN4) as a critical regulator of M1 macrophage polarization and RA pathogenesis. In a collagen-induced arthritis (CIA) model established in male DBA/1J mice and a collagen antibody-induced arthritis (CAIA) model constructed using KCNN4 myeloid-specific knockout mice and their littermate controls, pharmacological inhibition of KCa3.1 using TRAM-34 or genetic ablation of KCNN4 significantly reduced clinical arthritis scores, attenuated joint swelling, synovial hyperplasia, inflammatory cell infiltration, cartilage damage, and bone erosion. In vitro, pharmacological blockade of KCa3.1 suppressed lipopolysaccharide (LPS) and interferon-γ (IFN-γ) induced M1 polarization in bone marrow-derived macrophages (BMDMs) and RAW264.7 cells, evidenced by reduced expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), as well as decreased production of inflammatory cytokines. Mechanistically, we reveal that KCa3.1 facilitates NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, a key driver of macrophage inflammatory responses, and that its inhibition attenuates NLRP3 expression, caspase-1 activation, and IL-1β secretion. These findings establish that KCa3.1 promotes RA progression by enhancing NLRP3-mediated M1 macrophage polarization. Moreover, transient receptor potential melastatin-subfamily member 7 (TRPM7) potentiates KCa3.1-mediated NLRP3 inflammasome activation. Thus, targeting KCa3.1 may represent a promising therapeutic strategy to rebalance macrophage phenotypes, suppress chronic inflammation, and halt RA progression.