ASIC1a induces synovial inflammation via the Ca²⁺/NFATc3/ RANTES pathway

Abstract

Rationale: Synovial inflammation is one of the main pathological features of rheumatoid arthritis (RA) and is a key factor leading to the progression of RA. Understanding the regulatory mechanism of synovial inflammation is crucial for the treatment of RA. Acid-sensing ion channel 1a (ASIC1a) is an H+-gated cation channel that promotes the progression of RA, but the role of ASIC1a in synovial inflammation is unclear. This study aimed to investigate whether ASIC1a is involved in the synovial inflammation and explore the underlying mechanisms in vitro and in vivo.Methods: The expression of ASIC1a and nuclear factor of activated T cells (NFATs) were analyzed by Western blotting, immunofluorescence, and immunohistochemistry both in vitro and in vivo. The Ca2+ influx mediated by ASIC1a was detected by calcium imaging and flow cytometry. The role of ASIC1a in inflammation was studied in rats with adjuvant-induced arthritis (AA). Inflammatory cytokine profile was analyzed by protein chip in RA synovial fibroblasts (RASF) and verified by a magnetic multi-cytokine assay and ELISA. The NFATc3-regulated RANTES (Regulated upon activation, normal T cell expressed and secreted) gene transcription was investigated by ChIP-qPCR and dual-luciferase reporter assay.Results: The expression of ASIC1a was significantly increased in human RA synovial tissues and primary human RASF as well as in ankle synovium of AA rats. Activated ASIC1a mediated Ca2+ influx to increase [Ca2+]i in RASF. The activation/overexpression of ASIC1a in RASF up-regulated the expression of inflammatory cytokines RANTES, sTNF RI, MIP-1a, IL-8, sTNF RII, and ICAM-1 among which RANTES was increased most remarkably. In vivo, ASIC1a promoted inflammation, synovial hyperplasia, articular cartilage, and bone destruction, leading to the progression of AA. Furthermore, activation of ASIC1a upregulated the nuclear translocation of NFATc3, which bound to RANTES promoter and directly regulated gene transcription to enhance RANTES expression.Conclusion: ASIC1a induces synovial inflammation, which leads to the progression of RA. Our study reveals a novel RA inflammation regulatory mechanism and indicates that ASIC1a might be a potential therapeutic target for RA.

Acid‐sensing ion channel 1a mediates acid‐induced pyroptosis through calpain‐2/calcineurin pathway in rat articular chondrocytes

“…In the past 2 years, our research team has shown that activated ASIC1a induces autophagy, synovial invasion, and synovial inflammation by mediating calcium influx (Gao, Xu, Ge, & Chen, 2019; Niu et al, 2020; Zhang et al, 2020). Calpains are ubiquitous calcium‐activated cysteine proteases.…”

Acid-Sensing Ion Channel-1a in Articular Chondrocytes and Synovial Fibroblasts: A Novel Therapeutic Target for Rheumatoid Arthritis

“…In a study, a reduction in pH was detected in the synovial fluid of AA rats, and ASIC1a was upregulated in AA rat articular chondrocytes in vivo ( 4 ). Further studies have indicated that the expression level of ASIC1a is increased in the synovial tissues of AA rats than in normal rats, suggesting that ASIC1a may be involved in the pathological process of RA ( 18 , 19 ).…”

“…In a previous study, we found that ASIC1a, ASIC2a, and ASIC3 were expressed in the articular chondrocytes of rats with AA, and that the expression levels of ASIC1awere significantly higher than those of other subunits ( 4 ). More recently, it has been reported that the expression of ASIC1a is significantly increased in human RA synovial tissues, primary human RASF, and the ankle synovium of AA rats ( 18 , 19 ). Table 1 summarizes the tissue and cell distribution of ASIC1a.…”

“…PCTX1, a peptide purified from the venom of the southern spider tarantula Psalmopoeus cambridgei , can specifically and strongly inhibit the current of ASIC1a ( 64 , 65 ). Moreover, studies have suggested that PCTX1 can block ASIC1a in articular chondrocytes and RASF in vitro ( 4 , 18 , 19 , 66 ).…”

“…There is growing evidence that activated RASF, a critical component of the synovial tissue to investigate the mechanism of synovial inflammation, plays a crucial role in the pathogenesis of joint destruction and RA ( 82 ). Moreover, membrane ASIC1a has been reported to be highly expressed in the RASF of three donors compared to the normal synovial fluid (NSF) of a donor ( 18 ).…”