神经炎症
小胶质细胞
糖酵解
缺血
细胞生物学
己糖激酶
缺氧(环境)
基因敲除
体内
厌氧糖酵解
脑缺血
半影
生物
神经科学
化学
药理学
医学
炎症
生物化学
免疫学
酶
内科学
细胞凋亡
氧气
有机化学
生物技术
作者
Yuan Li,Bingzheng Lu,Longxiang Sheng,Zhu Zhu,Hongjiaqi Sun,Yuwei Zhou,Yang� Yang,Dongdong Xue,Wenli Chen,Xiaoli Tian,Youwei Du,Min Yan,Wenbo Zhu,Fan Xing,Kai Li,Lin Su,Pengxin Qiu,Xingwen Su,Yijun Huang,Yan Gao,Wei Yin
摘要
Hyperglycolysis, observed within the penumbra zone during brain ischemia, was shown to be detrimental for tissue survival because of lactate accumulation and reactive oxygen species overproduction in clinical and experimental settings. Recently, mounting evidence suggests that glycolytic reprogramming and induced metabolic enzymes can fuel the activation of peripheral immune cells. However, the possible roles and details regarding hyperglycolysis in neuroinflammation during ischemia are relatively poorly understood. Here, we investigated whether overactivated glycolysis could activate microglia and identified the crucial regulators of neuroinflammatory responses in vitro and in vivo. Using BV 2 and primary microglial cultures, we found hyperglycolysis and induction of the key glycolytic enzyme hexokinase 2 (HK2) were essential for microglia-mediated neuroinflammation under hypoxia. Mechanistically, HK2 up-regulation led to accumulated acetyl-coenzyme A, which accounted for the subsequent histone acetylation and transcriptional activation of interleukin (IL)-1β. The inhibition and selective knockdown of HK2 in vivo significantly protected against ischemic brain injury by suppressing microglial activation and IL-1β production in male Sprague-Dawley rats subjected to transient middle cerebral artery occlusion (MCAo) surgery. We provide novel insights for HK2 specifically serving as a neuroinflammatory determinant, thus explaining the neurotoxic effect of hyperglycolysis and indicating the possibility of selectively targeting HK2 as a therapeutic strategy in acute ischemic stroke.
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