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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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6929608 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Zhang Yihao Y Qian Xuewen X Yang Xiaojuan X Niu Ruowen R Song Sujing S Zhu Fei F Zhu Chuanjun C Peng Xiaoqing X Chen Feihu F

Theranostics 20200101 1

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 ...[more]

PMID: 31903118

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Project description:Tick-borne encephalitis virus (TBEV) is one of the most important flaviviruses that targets the central nervous system (CNS) and causes encephalitides in humans. Although neuroinflammatory mechanisms may contribute to brain tissue destruction, the induction pathways and potential roles of specific chemokines in TBEV-mediated neurological disease are poorly understood.BALB/c mice were intracerebrally injected with TBEV, followed by evaluation of chemokine and cytokine profiles using protein array analysis. The virus-infected mice were treated with the CC chemokine antagonist Met-RANTES or anti-RANTES mAb to determine the role of RANTES in affecting TBEV-induced neurological disease. The underlying signaling mechanisms were delineated using RANTES promoter luciferase reporter assay, siRNA-mediated knockdown, and pharmacological inhibitors in human brain-derived cell culture models.In a mouse model, pathological features including marked inflammatory cell infiltrates were observed in brain sections, which correlated with a robust up-regulation of RANTES within the brain but not in peripheral tissues and sera. Antagonizing RANTES within CNS extended the survival of mice and reduced accumulation of infiltrating cells in the brain after TBEV infection. Through in vitro studies, we show that virus infection up-regulated RANTES production at both mRNA and protein levels in human brain-derived cell lines and primary progenitor-derived astrocytes. Furthermore, IRF-3 pathway appeared to be essential for TBEV-induced RANTES production. Site mutation of an IRF-3-binding motif abrogated the RANTES promoter activity in virus-infected brain cells. Moreover, IRF-3 was activated upon TBEV infection as evidenced by phosphorylation of TBK1 and IRF-3, while blockade of IRF-3 activation drastically reduced virus-induced RANTES expression.Our findings together provide insights into the molecular mechanism underlying RANTES production induced by TBEV, highlighting its potential importance in the process of neuroinflammatory responses to TBEV infection.

Project description:Regulated on activation, normal T expressed, and secreted (RANTES)/CC ligand 5 (CCL5) participates in rheumatoid arthritis (RA) pathogenesis by facilitating leukocyte infiltration, however, its other pathological functions are not fully defined in RA. In the present study, we evaluated the effect of RANTES/CCL5 on tissue degrading enzymes matrix metalloproteinase-1 (MMP-1) and MMP-13 expression and its contribution to the progressive joint damage by RA synovial fibroblasts (RASFs). Our results showed that RANTES/CCL5 dose dependently induced MMP-1 and MMP-13 expression in monolayers and three-dimensional (3D) micromass of human RASFs, which correlated with an increase in collagenase activity. This activation by RANTES/CCL5 was observed in RASF, but not in osteoarthritis SFs (OASFs). Evaluation of the signaling events showed that RANTES/CCL5 selectively activated PKC?, JNK, and ERK proteins to induce MMP expression in human RASFs. Pretreatment with a functional antagonist (Met-RANTES) or heparinase III [an enzyme that selectively digests heparan sulfate proteoglycans (HSPGs)] completely abrogated RANTES/CCL5-induced MMP-1 and MMP-13 expression. Interestingly, the inhibition of RANTES/CCL5 using small-interfering RNA approach reduced the ability of interleukin-1? (IL-1?) to induce MMP-1 and MMP-13 expression, asserting its mediatory role in tissue remodeling. In the inhibitor study, only the selective inhibition of HSPGs or PKC?, ERK, and JNK markedly inhibited RANTES/CCL5-induced MMP-1 and MMP-13 production. Circular dichroism spectroscopy results demonstrated the degradation of collagen triple-helical structure upon exposure to the conditioned media from RANTES/CCL5 stimulated RASFs, which was reverted by a broad-spectrum MMP inhibitor (GM6001). These findings suggest that RANTES/CCL5 not only upregulates MMP-1 and MMP-13 expression by partly utilizing HSPGs and/or PKC?-JNK/ERK pathways but also mediates IL-1?-induced MMP-1 and MMP-13 expression.

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

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ASIC1a induces synovial inflammation via the Ca<sup>2+</sup>/NFATc3/ RANTES pathway.

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