Neuroinflammation, especially activation of microglia, the key immune cells in the brain, has been proposed to contribute to the pathogenesis of ischemic stroke. However, the dynamics and the potential mediators of microglial activation following ischemic neuronal injury are not well understood. In this study, using oxygen/glucose deprivation and reoxygenation with neuronal and microglial cell cultures as an in vitro model of ischemic neuronal injury, we set out to identify neuronal factors released from injured neurons that are capable of inducing microglial activation. Conditioned media (CM) from hippocampal and cortical neurons exposed to oxygen/glucose deprivation and reoxygenation induced significant activation of microglial cells as well as primary microglia, evidenced by up-regulation of inducible nitric oxide synthase, increased production of nitrite and reactive oxygen species, and increased expression of microglial markers. Mechanistically, neuronal ischemia-responsive protein 94 (Irp94) was a key contributor to microglial activation since significant increase in Irp94 was detected in the neuronal CM following ischemic insult and immunodepletion of Irp94 rendered ischemic neuronal CM ineffective in inducing microglial activation. Ischemic insult-augmented oxidative stress was a major facilitator of neuronal Irp94 release, and pharmacological inhibition of NADPH oxidase significantly reduced the ischemic injury-induced neuronal reactive oxygen species production and Irp94 release. Taken together, these results indicate that neuronal Irp94 may play a pivotal role in the propagation of ischemic neuronal damage. Continued studies may help identify Irp94 and/or related proteins as potential therapeutic targets and/or diagnostic/prognostic biomarkers for managing ischemia-associated brain disorders.

译文

已经提出:神经炎症,特别是小胶质细胞的激活,小胶质细胞是大脑中的关键免疫细胞,有助于缺血性中风的发病。然而,尚不清楚缺血性神经元损伤后小胶质细胞激活的动力学和潜在的介质。在这项研究中,将缺氧/葡萄糖剥夺和再充氧与神经元和小胶质细胞培养物一起用作缺血性神经元损伤的体外模型,我们着手确定从受伤的神经元释放的能够诱导小胶质细胞活化的神经元因子。来自暴露于氧气/葡萄糖剥夺和再充氧的海马和皮质神经元的条件培养基(CM)诱导了小胶质细胞以及原代小胶质细胞的显着活化,这可通过诱导型一氧化氮合酶的上调,亚硝酸盐和活性氧的产生增加来证明,并增加小胶质细胞标志物的表达。从机理上讲,神经元缺血响应蛋白94(Irp94)是小胶质细胞激活的关键因素,因为在缺血性损伤后神经元CM中检测到Irp94的显着增加,并且Irp94的免疫耗竭使得缺血性神经元CM不能诱导小胶质细胞激活。缺血性损伤加剧的氧化应激是神经元Irp94释放的主要促进因素,并且NADPH氧化酶的药理抑制作用显着降低了缺血性损伤诱导的神经元活性氧的产生和Irp94的释放。综上,这些结果表明神经元Irp94可能在缺血性神经元损伤的传播中起关键作用。继续进行的研究可能有助于将Irp94和/或相关蛋白鉴定为潜在的治疗靶标和/或诊断/预后生物标记物,以治疗与缺血相关的脑部疾病。

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