HIF-1α Mediates TRAIL-Induced Neuronal Apoptosis via Regulating DcR1 Expression Following Traumatic Brain Injury

Yuanjian Fang; Jianan Lu; Xiaoyu Wang; Haijian Wu; Shuhao Mei; Jingwei Zheng; Shenbin Xu; Cameron Lenahan; Sheng Chen; Jianmin Zhang; Yuan Hong

doi:10.3389/fncel.2020.00192

HIF-1α Mediates TRAIL-Induced Neuronal Apoptosis via Regulating DcR1 Expression Following Traumatic Brain Injury

Front Cell Neurosci. 2020 Aug 3:14:192. doi: 10.3389/fncel.2020.00192. eCollection 2020.

Authors

Yuanjian Fang¹, Jianan Lu¹, Xiaoyu Wang¹, Haijian Wu¹, Shuhao Mei¹, Jingwei Zheng¹, Shenbin Xu¹, Cameron Lenahan^{2

3}, Sheng Chen¹, Jianmin Zhang^{1

4

5}, Yuan Hong¹

Affiliations

¹ Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA, United States.
³ Burrell College of Osteopathic Medicine, Las Cruces, NM, United States.
⁴ Brain Research Institute, Zhejiang University, Hangzhou, China.
⁵ Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, China.

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.

Keywords: death receptor 5; decoy receptor; hypoxia-induced factor-1α; traumatic brain injury; tumor necrosis factor-related apoptosis-inducing ligand.