MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson's disease.
MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson's disease.
复制标题
MicroRNA-7靶向Nod样受体蛋白3炎症小体调节帕金森病发病机制中的神经炎症
DOI：
10.1186/s13024-016-0094-3
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发表时间：
2016-04-16
影响因子：
15.1
通讯作者：
Hu G
中科院分区：
文献类型：
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作者：
Zhou Y;Lu M;Du RH;Qiao C;Jiang CY;Zhang KZ;Ding JH;Hu G
α-突触核蛋白(α-Syn)是帕金森病(PD)的病理标志，已被认为在一个至少在体外依赖于单核细胞中Nod样受体蛋白3(NLRP3)炎症小体的过程中诱导IL-1β的产生。然而，NLRP3炎性小体激活在帕金森病发病中的作用尚未完全确定。在本研究中，我们发现NLRP3炎性小体在帕金森病患者的血清和帕金森病模型小鼠的中脑中被激活。我们进一步阐明了α-SYN通过小胶质细胞内吞和随后的溶酶体组织蛋白B释放激活了NLRP3炎症小体。NLRP3炎症体的重要组成部分Caspase-1的缺失显著抑制了α-SYN诱导的小胶质细胞活化和白介素1β的产生，从而减轻了小胶质细胞介质处理的中脑多巴胺能神经元的减少。具体来说，我们首次证明了Nlrp3是microRNA-7(miR-7)的靶基因。在体外，miR-7可抑制小胶质细胞NLRP3炎性小体的激活，而抗miR-7可加重炎性小体的激活。值得注意的是，在MPTP诱导的帕金森病模型小鼠中，立体定向注射miR-7模拟小鼠纹状体，减轻了多巴胺能神经元的变性，同时改善了小胶质细胞的激活。我们的研究提供了miR-7和NLRP3炎症小体介导的神经炎症在帕金森病发病机制中的直接联系。这些发现将使我们深入了解miR-7和NLRP3炎症体在开辟PD治疗新途径方面的潜力。本文的在线版本(doi：10.1186/s13024-0160094-3)包含补充材料，授权用户可以使用。
α-Synuclein (α-Syn), a pathological hallmark of Parkinson’s disease (PD), has been recognized to induce the production of interleukin-1β in a process that depends, at least in vitro, on nod-like receptor protein 3 (NLRP3) inflammasome in monocytes. However, the role of NLRP3 inflammasome activation in the onset of PD has not yet been fully established. In this study, we showed that NLRP3 inflammasomes were activated in the serum of PD patients and the midbrain of PD model mice. We further clarified that α-syn activated the NLRP3 inflammasome through microglial endocytosis and subsequent lysosomal cathepsin B release. Deficiency of caspase-1, an important component of NLRP3 inflammasome, significantly inhibited α-syn-induced microglia activation and interleukin-1β production, which in turn alleviated the reduction of mesencephalic dopaminergic neurons treated by microglia medium. Specifically, we demonstrated for the first time that Nlrp3 is a target gene of microRNA-7 (miR-7). Transfection of miR-7 inhibited microglial NLRP3 inflammasome activation whereas anti-miR-7 aggravated inflammasome activation in vitro. Notably, stereotactical injection of miR-7 mimics into mouse striatum attenuated dopaminergic neuron degeneration accompanied by the amelioration of microglial activation in MPTP-induced PD model mice. Our study provides a direct link between miR-7 and NLRP3 inflammasome-mediated neuroinflammation in the pathogenesis of PD. These findings will give us an insight into the potential of miR-7 and NLRP3 inflammasome in terms of opening up novel therapeutic avenues for PD. The online version of this article (doi:10.1186/s13024-016-0094-3) contains supplementary material, which is available to authorized users.