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HIF-1α Mediates TRAIL-Induced Neuronal Apoptosis via Regulating DcR1 Expression Following Traumatic Brain Injury.
Frontiers in Cellular Neuroscience ( IF 4.2 ) Pub Date : 2020-06-02 , DOI: 10.3389/fncel.2020.00192
Yuanjian Fang 1 , Jianan Lu 1 , Xiaoyu Wang 1 , Haijian Wu 1 , Shuhao Mei 1 , Jingwei Zheng 1 , Shenbin Xu 1 , Cameron Lenahan 2, 3 , Sheng Chen 1 , Jianmin Zhang 1, 4, 5 , Yuan Hong 1
Affiliation  

Background: Neuronal apoptosis involved in secondary injury following traumatic brain injury (TBI) significantly contributes to the poor outcomes of patients with TBI. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis of tumor cells. Hypoxia factor (HIF) 1α is a controversial factor that mediates the neuronal apoptotic pathway. Herein, we hypothesize that HIF-1α may mediate the TRAIL-induced neuronal apoptosis after TBI.

Methods: We used Western blots and immunofluorescence to study the expression and cell localization of TRAIL and death receptor 5 (DR5) after TBI in rats. Soluble DR5 (sDR5) administration was used to block the TRAIL-induced neuronal death and neural deficits. HIF-1α inhibitor 2ME and agonist DMOG were used to study the role of HIF-1α in TRAIL-induced neuronal death. Meanwhile, HIF-1α siRNA was used to investigate the role of HIF-1α in TRAIL-induced neuronal death in vitro.

Results: The expressions of microglia-located TRAIL and neuron-located DR5 were significantly upregulated after TBI. sDR5 significantly attenuated TRAIL-induced neuronal apoptosis and neurological deficits. 2ME decreased neuronal apoptosis, lesion area, and brain edema and improved neurological function via increased expression of TRAIL decoy receptor 1 (DcR1), which inhibited TRAIL-induced apoptosis after TBI. The administration of DMOG produced the opposite effect than did 2ME. Similarly, HIF-1α siRNA attenuated TRAIL-induced neuronal death via increased DcR1 expression in vitro.

Conclusion: Our findings suggested that the TRAIL/DR5 signaling pathway plays an important role after neuronal apoptosis after TBI. HIF-1α mediates TRAIL-induced neuronal apoptosis by regulating DcR1 expression following TBI.



中文翻译:

HIF-1α通过调节脑外伤后DcR1的表达介导TRAIL诱导的神经元凋亡。

背景:创伤性脑损伤(TBI)后继发性损伤所涉及的神经元凋亡是导致TBI患者不良预后的重要原因。肿瘤坏死因子相关的凋亡诱导配体(TRAIL)可以选择性诱导肿瘤细胞的凋亡。缺氧因子(HIF)1α是介导神经元凋亡途径的有争议的因子。本文中,我们假设HIF-1α可能介导TBI后TRAIL诱导的神经元凋亡。

方法:我们使用蛋白质印迹和免疫荧光研究了大鼠TBI后TRAIL和死亡受体5(DR5)的表达和细胞定位。可溶性DR5(sDR5)的给药被用于阻断TRAIL诱导的神经元死亡和神经缺陷。使用HIF-1α抑制剂2ME和激动剂DMOG来研究HIF-1α在TRAIL诱导的神经元死亡中的作用。同时,使用了HIF-1αsiRNA来研究HIF-1α在TRAIL诱导的神经元死亡中的作用。体外

结果:TBI后小胶质细胞TRAIL和神经元DR5的表达明显上调。sDR5显着减弱了TRAIL诱导的神经元凋亡和神经功能缺损。2ME减少神经元凋亡,病变区域和脑水肿并改善神经功能通过增加TRAIL诱饵受体1(DcR1)的表达,抑制TBI后TRAIL诱导的细胞凋亡。DMOG的施用产生了与2ME相反的作用。同样,HIF-1αsiRNA减轻TRAIL诱导的神经元死亡通过 DcR1表达增加 体外

结论:我们的发现表明,TBI后神经元凋亡后,TRAIL / DR5信号通路起着重要作用。HIF-1α通过调节TBI后的DcR1表达来介导TRAIL诱导的神经元凋亡。

更新日期:2020-08-03
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