Dual Role of Triptolide in Interrupting the NLRP3 Inflammasome Pathway to Attenuate Cardiac Fibrosis
Dual Role of Triptolide in Interrupting the NLRP3 Inflammasome Pathway to Attenuate Cardiac Fibrosis
复制标题
雷公藤甲素在阻断 NLRP3 炎症小体途径以减轻心脏纤维化方面的双重作用
DOI：
10.3390/ijms20020360
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发表时间：
2019-01-02
影响因子：
5.6
通讯作者：
Zhang, Hai-Gang
中科院分区：
文献类型：
--
作者：
Pan, Xi-Chun;Liu, Ya;Zhang, Hai-Gang
在之前的一篇论文中，我们报道了雷公藤甲素（TP），一种常用的免疫调节剂，可以减轻心脏肥厚。本研究旨在从nod样受体蛋白3 （NLRP3）炎性体的角度进一步探讨TP对心脏纤维化的抑制作用及其可能机制。采用苏木精-伊红染色、马松染色、免疫组化、免疫荧光法观察小鼠和小鼠心脏成纤维细胞（CFs）的心肌纤维化变化。Western blot、共定位和免疫沉淀检测蛋白表达和相互作用。结果表明，TP剂量依赖性地抑制异丙肾上腺素诱导的心肌纤维化和血管紧张素II诱导的CFs胶原生成。TP通过抑制NLRP3炎性小体的激活表现出抗纤维化作用，从而降低IL-1β成熟、髓样分化因子88 （MyD88）相关的c-Jun n -末端激酶（JNK）磷酸化、细胞外调节蛋白激酶1/2 （ERK1/2）和TGF-β1/Smad信号，最终导致胶原生成减少。此外，TP在nlrp3敲除的CFs中没有抗纤维化作用。值得注意的是，TP通过阻断NLRP3-ASC相互作用来抑制炎性小体的激活，从而抑制NLRP3和含有caspase募集域（ASC）的凋亡相关斑点样蛋白的表达以及炎性小体的组装。最后，TP在体内确实抑制了nlrp3 - tgf - β1- smad通路。最后，TP被发现在阻断NLRP3炎性体的激活以减轻心脏纤维化方面发挥双重作用。
In a previous paper, we reported that triptolide (TP), a commonly used immunomodulator, could attenuate cardiac hypertrophy. This present study aimed to further explore the inhibition of cardiac fibrosis by TP and the possible mechanism from the perspective of the NOD-like receptor protein 3 (NLRP3) inflammasome. Hematoxylin-eosin and Masson’s staining, immunohistochemistry, and immunofluorescence were performed to observe cardiac fibrotic changes in mice and mouse cardiac fibroblasts (CFs). The Western blot, colocalization, and immunoprecipitation were applied to detect protein expression and interactions. Results suggested that TP dose-dependently inhibited cardiac fibrosis induced by isoproterenol and collagen production of CFs induced by angiotensin II. TP exhibited an antifibrotic effect via inhibiting activation of the NLRP3 inflammasome, which sequentially decreased IL-1β maturation, myeloid differentiation factor 88 (MyD88)-related phosphorylation of c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase 1/2 (ERK1/2), and TGF-β1/Smad signaling, and ultimately resulted in less collagen production. Moreover, TP showed no antifibrotic effect in Nlrp3-knockout CFs. Notably, TP inhibited the expression of NLRP3 and apoptosis-associated speck-like proteins containing a caspase recruitment domain (ASC) as well as inflammasome assembly, by interrupting the NLRP3-ASC interaction to inhibit inflammasome activation. Finally, TP indeed inhibited the NLRP3-TGFβ1-Smad pathway in vivo. Conclusively, TP was found to play a dual role in interrupting the activation of the NLRP3 inflammasome to attenuate cardiac fibrosis.