NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke
NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke
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NLRP3缺陷可改善实验性缺血性中风的神经血管损伤
DOI：
10.1038/jcbfm.2013.242
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发表时间：
2014-04-01
影响因子：
6.3
通讯作者：
Yi, Fan
中科院分区：
文献类型：
--
作者：
Yang, Fan;Wang, Ziying;Yi, Fan
虽然诱导缺血后炎症反应的先天免疫应答被认为是脑缺血损伤进展中的重要步骤，但先天免疫介质NLRP 3在缺血性卒中发病机制中的作用尚不清楚。在这项研究中，局灶性缺血是由大脑中动脉闭塞NLRP 3（-/-），NOX 2（-/-），或野生型（WT）小鼠。通过磁共振成像（MRI）、伊文思蓝通透性和电镜分析，我们发现NLRP 3缺陷通过减少梗死和血脑屏障（BBB）损伤来改善缺血性中风后小鼠的脑损伤。我们进一步表明，NLRP 3对神经血管损伤的贡献与NLRP 3介导的白细胞介素-1 β（IL-1 β）释放的自分泌/旁分泌模式相关，这一点可以通过增加脑微血管内皮细胞通透性和小胶质细胞介导的神经毒性来证明。最后，我们发现NOX 2缺乏通过介导NLRP 3信号传导改善缺血性卒中后的预后。这项研究首次显示了NLRP 3对神经血管损伤的贡献，并提供了直接证据表明NLRP 3作为一种重要的靶分子将NOX 2介导的氧化应激与缺血性卒中中的神经血管损伤联系起来。药理学靶向NLRP 3介导的炎症反应在多个水平可能有助于设计一种新的方法来开发治疗策略，用于预防脑功能恶化和治疗中风。
Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3(-/-), NOX2(-/-), or wild-type (WT) mice. By magnetic resonance imaging (MRI), Evans blue permeability, and electron microscopic analyses, We found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3-mediated interleukin-1 beta (IL-1 beta) release as evidenced by increased brain microvessel endothelial cell permeability and microglia-mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2-mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.