Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury
Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury
复制标题
脑缺血/再灌注损伤过程中线粒体功能障碍诱导NLRP3炎症小体激活
DOI：
10.1186/s12974-018-1282-6
复制
发表时间：
2018-08-28
影响因子：
9.3
通讯作者：
Peng, Ying
中科院分区：
文献类型：
--
作者：
Gong, Zhe;Pan, Jingrui;Peng, Ying
背景：nod样受体蛋白3 （NLRP3）炎症小体是脑缺血再灌注（I/R）后介导炎症反应的关键因子，但NLRP3炎症小体在脑缺血再灌注中的细胞定位尚未得出结论，线粒体与NLRP3炎症小体在脑缺血再灌注中的关系尚没有明确的证据。方法：本研究在缺氧-葡萄糖剥夺/再氧化（OGD/R）条件下，在短暂性大脑中动脉闭塞（tMCAO）大鼠模型和transwell共培养细胞系统中检测NLRP3炎症小体的细胞定位。然后，我们研究了OGD/R和脑I/R损伤后不同细胞类型中线粒体功能障碍与NLRP3炎症小体激活的关系。结果：我们的研究结果显示，NLRP3炎性小体在脑I/R损伤发生后不久首先在小胶质细胞中被激活，随后在神经元和微血管内皮细胞中表达，但主要在神经元中表达。此外，线粒体功能障碍在OGD/R后小胶质细胞NLRP3炎症小体的激活中起重要作用，线粒体保护剂可以抑制脑I/R大鼠NLRP3炎症小体的激活。结论：我们的研究结果可能为NLRP3炎症小体在脑I/R损伤不同阶段的细胞类型依赖性激活以及线粒体功能障碍在NLRP3炎症小体通路激活中的作用提供新的见解。
Background: Nod-like receptor protein 3 (NLRP3) inflammasome is a crucial factor in mediating inflammatory responses after cerebral ischemia/reperfusion (I/R), but the cellular location of NLRP3 inflammasome in cerebral I/R has yet come to a conclusion, and there is still no specific evidence to state the relationship between mitochondria and the NLRP3 inflammasome in cerebral I/R.Methods: In the present study, we detected the cellular localization of NLRP3 inflammasomes in a transient middle cerebral artery occlusion (tMCAO) rat model and a transwell co-culture cell system under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Then, we investigated the relationship between mitochondrial dysfunction and the activation of NLRP3 inflammasomes in different cell types after OGD/R and cerebral I/R injury.Results: Our results showed that NLRP3 inflammasomes were first activated in microglia soon after cerebral I/R injury onset and then were expressed in neurons and microvascular endothelial cells later, but they were mainly in neurons. Furthermore, mitochondrial dysfunction played an important role in activating NLRP3 inflammasomes in microglia after OGD/R, and mitochondrial protector could inhibit the activation of NLRP3 inflammasomes in cerebral I/R rats.Conclusion: Our findings may provide novel insights into the cell type-dependent activation of NLRP3 inflammasomes at different stages of cerebral I/R injury and the role of mitochondrial dysfunction in activating the NLRP3 inflammasome pathway.