HIF-1α aggravated traumatic brain injury by NLRP3 inflammasome-mediated pyroptosis and activation of microglia

Hypoxia inducible factor 1 alpha (HIF-1 alpha) is involved in regulating the biological functions of neuronal death after traumatic brain injury (TBI), and attaches importance in the inflammatory response, but its potential mechanism is still unknown. Our study aimed to explore the regulatory mechanism between HIF-1 alpha and NLRP3 inflammasome after TBI. Male mice underwent controlled cortical impact (CCI) or sham-operated procedures. Brain water content and blood-brain barrier permeability were measured at the indicated time after TBI. The behavioral performance, ELISA, immunofluorescence, and western blot analysis were used to determine whether HIF-1 alpha specifically targeted TBI-induced pymptosis. We discovered that TBI-induced brain injury caused by external mechanical forces is characterized by edema and blood-brain barrier disorder, and the release of IL-1 beta, IL-18, and LDH and upregulation of HIF-1 alpha expression, reaching the peak on the third day post-TBI. In addition, HIF-1 alpha accumulated NLRP3 inflammasome-mediated pymptosis and activation of microglia. The protein expressions of NLRP3, GSDMD, GSDMD-N, pro-caspase 1, and cleaved caspase 1 were markedly increased in the injured cortex, which were restored to normal levels by the interference of HIF-1 alpha. The inactivation of HIF-1 alpha conferred neumprotection and alleviated brain injury after TBI. HIF-1 alpha was implicated in TBI-induced brain injury, aggravated NLRP3 inflammasome -mediated pymptosis, and the activation of microglia, which provided a potential target for treating TBI.

Automated summary

HIF-1α is involved in regulating neuronal death after TBI and inflammation, as shown in a study exploring the regulatory mechanism between HIF-1α and NLRP3 inflammasome. TBI-induced brain injury is characterized by edema, blood-brain barrier disorder, and an upregulation of HIF-1α expression. Inactivation of HIF-1α provided neuroprotection and alleviated brain injury post-TBI by attenuating NLRP3 inflammasome-mediated pyroptosis.