HIF-1α participates in secondary brain injury through regulating neuroinflammation

Xiaojian Xu; Mengshi Yang; Bin Zhang; Jinqian Dong; Yuan Zhuang; Qianqian Ge; Fei Niu; Baiyun Liu

doi:10.1515/tnsci-2022-0272

HIF-1α participates in secondary brain injury through regulating neuroinflammation

Transl Neurosci. 2023 Feb 9;14(1):20220272. doi: 10.1515/tnsci-2022-0272. eCollection 2023 Jan 1.

Authors

Xiaojian Xu¹, Mengshi Yang^{1

2}, Bin Zhang^{1

2}, Jinqian Dong^{1

2}, Yuan Zhuang^{1

2}, Qianqian Ge^{1

2}, Fei Niu¹, Baiyun Liu^{1

2

3

4}

Affiliations

¹ Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
² Beijing Key Laboratory of Central Nervous System Injury, Department of Neurosurgery, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.
³ Nerve Injury and Repair Center of Beijing Institute for Brain Disorders, Beijing, China.
⁴ China National Clinical Research Center for Neurological Diseases, Beijing, China.

Abstract

A deeper understanding of the underlying biological mechanisms of secondary brain injury induced by traumatic brain injury (TBI) will greatly advance the development of effective treatments for patients with TBI. Hypoxia-inducible factor-1 alpha (HIF-1α) is a central regulator of cellular response to hypoxia. In addition, growing evidence shows that HIF-1α plays the important role in TBI-induced changes in biological processes; however, detailed functional mechanisms are not completely known. The aim of the present work was to further explore HIF-1α-mediated events after TBI. To this end, next-generation sequencing, coupled with cellular and molecular analysis, was adopted to interrogate vulnerable events in a rat controlled cortical impact model of TBI. The results demonstrated that TBI induced accumulation of HIF-1α at the peri-injury site at 24 h post-injury, which was associated with neuronal loss. Moreover, gene set enrichment analysis unveiled that neuroinflammation, especially an innate inflammatory response, was significantly evoked by TBI, which could be attenuated by the inhibition of HIF-1α. Furthermore, the inhibition of HIF-1α could mitigate the activation of microglia and astrocytes. Taken together, all these data implied that HIF-1α might contribute to secondary brain injury through regulating neuroinflammation.

Keywords: 2-methoxyestradiol; GSEA; HIF-1α; apoptosis; controlled cortical impact; hypoxia; innate immune; neuroinflammation; secondary brain injury; traumatic brain injury.