Succinate/NLRP3 Inflammasome Induces Synovial Fibroblast Activation: Therapeutical Effects of Clematichinenoside AR on Arthritis.
Succinate/NLRP3 Inflammasome Induces Synovial Fibroblast Activation: Therapeutical Effects of Clematichinenoside AR on Arthritis.
复制标题
琥珀酸/NLRP3炎症小体诱导滑膜成纤维细胞活化：金线莲皂苷AR对关节炎的治疗作用
DOI：
10.3389/fimmu.2016.00532
复制
发表时间：
2016
影响因子：
7.3
通讯作者：
Liu LF
中科院分区：
文献类型：
--
作者：
Li Y;Zheng JY;Liu JQ;Yang J;Liu Y;Wang C;Ma XN;Liu BL;Xin GZ;Liu LF
威灵仙皂苷AR（C-AR）是从东北铁线莲（Clematis manshurica Rupr.）其为中医中用于治疗关节炎的草药。C-AR具有抗炎和免疫抑制特性，但对其抑制成纤维细胞活化的作用知之甚少。滑膜中的低氧张力和转化生长因子-β（TGF-β1）诱导导致关节炎纤维化。本研究从缺氧转化生长因子-β1（TGF-β1）和缺氧诱导转录因子-1 α（HIF-1α）的诱导作用方面探讨C-AR在滑膜纤维化中的作用。在类风湿性关节炎（RA）大鼠滑膜中，低氧TGF-β1诱导增加琥珀酸积累，这是由于琥珀酸脱氢酶（SDH）激活逆转所致，并以依赖于HIF-1α诱导的方式诱导NLRP 3炎性小体激活。响应于NLRP 3炎性体活化，释放的IL-1β进一步增加TGF-β1诱导，表明肌成纤维细胞活化中炎症和纤维化之间的正向循环。在RA大鼠滑膜中，C-AR通过抑制SDH活性抑制缺氧性TGF-β1诱导并抑制琥珀酸相关的NLRP 3炎性体活化，从而通过阻断炎症和纤维化之间的相互作用防止肌成纤维细胞活化。综上所述，这些结果表明，琥珀酸作为代谢信号，通过NLRP 3炎性小体激活将炎症与纤维化联系起来。这些结果表明，滑膜琥珀酸积累和HIF-1α诱导可能是预防关节炎纤维化的治疗靶点。
Clematichinenoside AR (C-AR) is a triterpene saponin isolated from the root of Clematis manshurica Rupr., which is a herbal medicine used in traditional Chinese medicine for the treatment of arthritis. C-AR exerts anti-inflammatory and immunosuppressive properties, but little is known about its action in the suppression of fibroblast activation. Low oxygen tension and transforming growth factor-β (TGF-β1) induction in the synovium contribute to fibrosis in arthritis. This study was designed to investigate the effect of C-AR on synovial fibrosis from the aspects of hypoxic TGF-β1 and hypoxia-inducible transcription factor-1α (HIF-1α) induction. In the synovium of rheumatoid arthritis (RA) rats, hypoxic TGF-β1 induction increased succinate accumulation due to the reversal of succinate dehydrogenase (SDH) activation and induced NLRP3 inflammasome activation in a manner dependent on HIF-1α induction. In response to NLRP3 inflammasome activation, the released IL-1β further increased TGF-β1 induction, suggesting the forward cycle between inflammation and fibrosis in myofibroblast activation. In the synovium of RA rats, C-AR inhibited hypoxic TGF-β1 induction and suppressed succinate-associated NLRP3 inflammasome activation by inhibiting SDH activity, and thereby prevented myofibroblast activation by blocking the cross-talk between inflammation and fibrosis. Taken together, these results showed that succinate worked as a metabolic signaling, linking inflammation with fibrosis through NLRP3 inflammasome activation. These findings suggested that synovial succinate accumulation and HIF-1α induction might be therapeutical targets for the prevention of fibrosis in arthritis.
登录
查看更多内容
影响因子：
64.8
作者：
Vande Walle, Lieselotte;Van Opdenbosch, Nina;Jacques, Peggy;Fossoul, Amelie;Verheugen, Eveline;Vogel, Peter;Beyaert, Rudi;Elewaut, Dirk;Kanneganti, Thirumala-Devi;van Loo, Geert;Lamkanfi, Mohamed
通讯作者：
Lamkanfi, Mohamed
影响因子：
4.9
作者：
Giatromanolaki, A;Sivridis, E;Koukourakis, MI
通讯作者：
Koukourakis, MI
影响因子：
3.7
作者：
Kim S;Hwang J;Xuan J;Jung YH;Cha HS;Kim KH
通讯作者：
Kim KH
影响因子：
5.4
作者：
Xiong, Ying;Ma, Yan;Li, Yun-Man
通讯作者：
Li, Yun-Man
影响因子：
13.3
作者：
Remst, D. F. G.;Blom, A. B.;van der Kraan, P. M.
通讯作者：
van der Kraan, P. M.