ASIC1a-CMPK2-mediated M1 macrophage polarization exacerbates chondrocyte senescence in osteoarthritis through IL-18

Purpose: Identification of a role for, and the mechanism of action of, the acid-sensing ion channel 1a (ASIC1a) in M1 macrophage polarization, which results in osteoarthritis (OA)-associated chondrocyte senescence. Method: ASIC1a expression in synovial M1 macrophages of OA patients was assessed by immunofluorescence. A role for ASIC1a in M1 macrophage and chondrocyte senescence was assessed in a mouse OA model. Results: ASIC1a expression was found to be upregulated in synovial M1 macrophages of OA patients. Extracellular acidification (pH 6.0) promoted M1 polarization of bone marrow derived macrophages (BMDMs), which was reversed by PcTx-1 or ASIC1a-siRNA. RNA-seq transcriptome results demonstrated a downregulation of M1 macrophage-associated genes in BMDMs after PcTx-1 treatment. Mechanistically, a role for the ASIC1a-cytidine/ uridine monophosphate kinase 2 (CMPK2) axis in M1 macrophage polarization was demonstrated. The concentration of IL-18 was elevated in synovial fluid and supernatants of acid-activated BMDMs. In vitro, IL-18 stimulation or co-culture with acid-activated macrophages promoted chondrocyte senescence. In vivo, intraarticular administration of PcTx-1 reduced articular cartilage destruction and chondrocytes senescence in OA mice, which related to reduced numbers of M1 macrophages and IL-18 in affected joints. Conclusion: These results demonstrate a novel pathogenic process that results in OA cartilage damage, in which M1 macrophage derived IL-18 induces articular chondrocytes senescence. Further, the ASIC1a-CMPK2 axis was shown to positively regulate M1 macrophage polarization. Hence, ASIC1a is a promising treatment target for M1 macrophage-mediated diseases, such as OA.