TIGAR inhibits ischemia/reperfusion-induced inflammatory response of astrocytes
TIGAR inhibits ischemia/reperfusion-induced inflammatory response of astrocytes
复制标题
TIGAR 抑制星形胶质细胞缺血/再灌注诱导的炎症反应
DOI：
10.1016/j.neuropharm.2018.01.012
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发表时间：
2018-03-15
影响因子：
4.7
通讯作者：
Qin, Zheng-Hong
中科院分区：
文献类型：
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作者：
Chen, Jieyu;Zhang, Ding-Mei;Qin, Zheng-Hong
脑缺血/再灌注损伤后，胶质细胞的炎症反应有助于神经元的损伤或修复。我们先前证明了TP 53诱导的糖酵解和凋亡调节因子（TIGAR）通过增加磷酸戊糖途径（PPP）的流量在缺血性神经元损伤中的保护作用。本研究探讨了TIGAR在缺血/再灌注诱导的星形胶质细胞炎症反应中的可能作用。雄性ICR小鼠大脑中动脉闭塞2 h，再灌注24 h，培养的原代星形胶质细胞缺氧缺糖9 h，再复氧24 h。腺病毒载体用于改变脑和培养的原代星形胶质细胞中TIGAR蛋白的水平。我们发现在OGD/R损伤期间，星形胶质细胞中TIGAR的蛋白水平迅速增加。TIGAR介导的过表达增加了培养的原代星形胶质细胞的活力、NADPH和rGSH水平，并减少了细胞内活性氧（ROS）。TIGAR的过表达不仅显著减少了卒中后的梗死体积，而且显著降低了长期死亡率并改善了神经功能的恢复。TIGAR的过度表达调节OGD/R-或缺血/再灌注诱导型一氧化氮合酶（iNOS），环氧合酶COX 2的上调和促炎细胞因子白细胞介素1 β（IL-1 β）和肿瘤坏死因子-α（TNF-α）的释放，而TIGAR敲低对这些参数产生相反的影响。此外，TIGAR过表达抑制OGD/R诱导的原代星形胶质细胞I κ B α降解和NF-κ B核转位。本研究阐明了TIGAR保护神经元免受缺血/再灌注损伤的新机制。(C)2018爱思唯尔有限公司版权所有。
The inflammatory response of glial cells contributes to neuronal damage or repair after brain ischemia/reperfusion insult. We previously demonstrated a protective role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in ischemic neuronal injury through increasing the flow of pentose phosphate pathway (PPP). The present study investigated the possible role of TIGAR in ischemia/reperfusion-induced inflammatory response of astrocytes. Male ICR mice were subjected to middle cerebral artery occlusion for 2 h followed by 24 h reperfusion and cultured primary astrocytes were subjected to oxygen glucose deprivation for 9 h followed by 24 h reoxygenation (OGD/R). Adenoviral vectors were used to alter the levels of TIGAR protein in brain and in culture primary astrocytes. We showed that during the OGD/R insult the protein levels of TIGAR were rapidly increased in astrocytes. Overexpression of TIGAR mediated increased the viability, levels of NADPH and rGSH, and reduced intracellular reactive oxygen species (ROS) in cultured primary astrocytes. Overexpression of TIGAR not only significantly reduced infarct volume after stroke insult but also markedly reduced long-term mortality and improved recovery of neurological functions. Overexpression of TIGAR tempered OGD/R- or ischemia/reperfusion-induced the upregulation of inducible nitric oxide synthase (iNOS), cyclooxygenases COX2 and the release of pro-inflammatory cytokines interleukin 1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), while TIGAR knockdown produced opposite effects on these parameters. Moreover, Overexpression of TIGAR suppressed OGD/R-induced degradation of I kappa B alpha and NF-kappa B nuclear translocation in cultured primary astrocytes. The present study elucidates a novel mechanism by which TIGAR protects neurons against ischemia/reperfusion injury. (C) 2018 Elsevier Ltd. All rights reserved.