Zhang Hongyu, Zhu Tianfeng, Liu Wenwen, Qu Xin, Chen Ye, Ren Ping, Wang Ziying, Wei Xinbing, Zhang Yan, Yi Fan
Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People's Republic of China.
Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, 250012, China.
J Mol Med (Berl). 2015 Sep;93(9):1033-43. doi: 10.1007/s00109-015-1288-9. Epub 2015 Apr 17.
Although recent studies have highlighted the importance of innate pattern-recognition receptors (PRRs) in the pathogenesis of cardiovascular diseases by mediating inflammatory responses, their molecular mechanisms of PRRs in cardiovascular diseases are still largely unknown. The present study was designed to explore the contribution of NOD2, an intracellular PRR, to the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. We found that NOD2 was upregulated in ischemic myocardium and NOD2 deficiency ameliorated cardiac injury in myocardial I/R mice accompanied by the decreased levels of pro-inflammatory mediators and cardiac inflammatory cell infiltration. We further found that TIPE2, a recently identified immune regulator, was negatively mediated by NOD2. In vitro, we demonstrated that TIPE2 inhibited NOD2-induced activation of MAPK and NF-κB signaling pathways, thereby reducing the production of pro-inflammatory cytokines in macrophages. Finally, in vivo gene silencing of TIPE2 by lentiviral gene delivery counteracted the reduced inflammation and myocardial injury in NOD2-deficient ischemic mice. Collectively, this study for the first time demonstrates that TIPE2 serves as a negative regulator of immunity, at least in part, by NOD2-mediated inflammatory responses in I/R-induced myocardial injury. A better understanding of NOD2-TIPE2 signaling pathways will provide unexpected opportunities for developing new therapies for ischemic cardiovascular disease.
NOD2 deficiency ameliorates myocardial ischemia reperfusion injury. NOD2 deficiency reduces the inflammatory response after myocardial I/R. TIPE2 inhibits NOD2-induced activation of MAPK and NF-κB signaling pathways. TIPE2 silencing counteracts the reduced inflammation and myocardial injury in NOD2(-/-) ischemic mice. TIPE2 acts as a negative regulator linking NOD2 and inflammatory responses.
尽管最近的研究强调了固有模式识别受体（PRR）通过介导炎症反应在心血管疾病发病机制中的重要性，但其在心血管疾病中的分子机制仍 largely 未知。本研究旨在探讨细胞内 PRR NOD2 对心肌缺血/再灌注（I/R）损伤发病机制的作用。我们发现 NOD2 在缺血心肌中上调，NOD2 缺陷改善了心肌 I/R 小鼠的心脏损伤，同时促炎介质水平降低和心脏炎症细胞浸润减少。我们进一步发现，最近鉴定出的免疫调节因子 TIPE2 被 NOD2 负向调节。在体外，我们证明 TIPE2 抑制 NOD2 诱导的 MAPK 和 NF-κB 信号通路激活，从而减少巨噬细胞中促炎细胞因子的产生。最后，通过慢病毒基因传递在体内对 TIPE2 进行基因沉默，抵消了 NOD2 缺陷缺血小鼠炎症和心肌损伤的减轻。总体而言，本研究首次证明 TIPE2 至少部分通过 NOD2 介导的 I/R 诱导心肌损伤中的炎症反应作为免疫负调节因子。更好地理解 NOD2-TIPE2 信号通路将为开发缺血性心血管疾病的新疗法提供意想不到的机会。
NOD2 缺陷改善心肌缺血再灌注损伤。NOD2 缺陷减少心肌 I/R 后的炎症反应。TIPE2 抑制 NOD2 诱导的 MAPK 和 NF-κB 信号通路激活。TIPE2 沉默抵消了 NOD2(-/-)缺血小鼠炎症和心肌损伤的减轻。TIPE2 作为连接 NOD2 和炎症反应的负调节因子。
