ASIC1a induces synovial inflammation via the Ca2+/NFATc3/ RANTES pathway
ASIC1a induces synovial inflammation via the Ca2+/NFATc3/ RANTES pathway
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ASIC1a 通过 Ca2 /NFATc3/ RANTES 途径诱导滑膜炎症
DOI：
10.7150/thno.37200
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Feihu Chen
中科院分区：
文献类型：
--
作者：
Yihao Zhang;Xuewen Qian;Xiaojuan Yang;Ruowen Niu;Sujing Song;Fei Zhu;Chuanjun Zhu;Xiaoqing Peng;Feihu Chen
基本原理：滑膜炎症是类风湿关节炎（RA）的主要病理特征之一，是导致RA进展的关键因素。了解滑膜炎症的调节机制对于RA的治疗至关重要。酸敏感离子通道1a（ASIC 1a）是一种H+门控阳离子通道，可促进RA的进展，但ASIC 1a在滑膜炎症中的作用尚不清楚。本研究旨在探讨ASIC 1a是否参与了滑膜炎症反应，并探讨其在体内外的作用机制。研究方法：采用免疫印迹、免疫荧光和免疫组织化学方法检测ASIC 1a和活化T细胞核因子（NFATs）的表达。采用钙离子成像和流式细胞术检测ASIC 1a介导的Ca 2+内流。本研究在实验性关节炎（AA）大鼠中研究了ASIC 1a在炎症中的作用。采用蛋白芯片技术检测RA滑膜成纤维细胞（RASF）中炎性细胞因子的表达，并采用磁性多细胞因子检测法和ELISA法进行验证。通过ChIP-qPCR和双荧光素酶报告基因分析研究NFATc 3调节的RANTES（Regulated upon activation，normal T cell expressed and secreted）基因转录。结果如下：ASIC 1a在人RA滑膜组织和原代人RASF以及AA大鼠踝关节滑膜中的表达显著增加。激活ASIC 1a可介导RASF内Ca ~（2+）内流增加[Ca ~（2+）] i。ASIC 1a在RASF中的激活/过表达上调了炎性细胞因子RANTES、sTNF RI、MIP-1a、IL-8、sTNF RII和ICAM-1的表达，其中RANTES的上调最为显著。在体内，ASIC 1a促进炎症、滑膜增生、关节软骨和骨破坏，导致AA的进展。ASIC 1a的激活可上调NFATc 3的核转位，使其与RANTES启动子结合，直接调控基因转录，增强RANTES表达。结论：ASIC 1a可诱导RA滑膜炎症反应，从而导致RA的进展。我们的研究揭示了一种新的RA炎症调节机制，并表明ASIC 1a可能是RA的潜在治疗靶点。
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.
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影响因子：
16.6
作者：
Klein-Hessling S;Muhammad K;Klein M;Pusch T;Rudolf R;Flöter J;Qureischi M;Beilhack A;Vaeth M;Kummerow C;Backes C;Schoppmeyer R;Hahn U;Hoth M;Bopp T;Berberich-Siebelt F;Patra A;Avots A;Müller N;Schulze A;Serfling E
通讯作者：
Serfling E
影响因子：
3.4
作者：
Yinger Huang;Songyuan Zheng;Ran Wang;Cuiping Tang;Junqing Zhu;Juan Li
通讯作者：
Yinger Huang;Songyuan Zheng;Ran Wang;Cuiping Tang;Junqing Zhu;Juan Li
DOI：
10.1074/jbc.m114.587865
发表时间：
2014-09-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Köck J;Kreher S;Lehmann K;Riedel R;Bardua M;Lischke T;Jargosch M;Haftmann C;Bendfeldt H;Hatam F;Mashreghi MF;Baumgrass R;Radbruch A;Chang HD
通讯作者：
Chang HD
影响因子：
12.4
作者：
Obry A;Hardouin J;Lequerré T;Jarnier F;Boyer O;Fardellone P;Philippe P;Marcelli C;Loët XL;Vittecoq O;Cosette P
通讯作者：
Cosette P
DOI：
10.1016/s0140-6736(94)92181-4
发表时间：
1994-05
期刊：
The Lancet
影响因子：
--
作者：
A. Whyte;R. Binns
通讯作者：
A. Whyte;R. Binns