ALPK1 regulates Synovitis in the Temporomandibular Joint via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization

ALPK1 (Alpha-kinase 1) was shown to be expressed on macrophages and associated with a variety of inflammatory diseases. The goal of this study was to clarify whether ALPK1 activation influences macrophage polarization, inducing inflammatory cytokine release and then contributes to synovial inflammation of TMJ. This study demonstrated that ALPK1 was highly upregulated not only in the synovial fluid of patients with TMJ synovitis, but also in the inflamed TMJ synovium of patients, especially located in synovial macrophages. Furthermore, ALPK1 knockout mice exhibited limited infiltration of macrophages and decreased expression levels of M1 macrophage-associated genes in CFA-induced TMJ inflammation. Meanwhile, our in-vitro study demonstrated that recombinant human ALPK1 (rhALPK1) could promote the expression of INOS, CD86, TNF-α, IL-1β and IL-6, and nuclear translocation of PKM2 in RAW264.7 cells. Besides, one of PKM2 agonists, DASA-58, significantly reversed the enhanced production of INOS, CD86, TNF-α, IL-1β and IL-6 induced by rhALPK1 in these cells. Collectively, we identified that the ALPK1 could regulate M1 macrophage polarization via promoting nuclear translocation of PKM2 and thereby contributing to development of TMJ synovitis.