AUTHOR=Fang Yuanjian , Lu Jianan , Wang Xiaoyu , Wu Haijian , Mei Shuhao , Zheng Jingwei , Xu Shenbin , Lenahan Cameron , Chen Sheng , Zhang Jianmin , Hong Yuan TITLE=HIF-1α Mediates TRAIL-Induced Neuronal Apoptosis via Regulating DcR1 Expression Following Traumatic Brain Injury JOURNAL=Frontiers in Cellular Neuroscience VOLUME=14 YEAR=2020 URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2020.00192 DOI=10.3389/fncel.2020.00192 ISSN=1662-5102 ABSTRACT=

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.