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Hexokinase 2‐dependent hyperglycolysis driving microglial activation contributes to ischemic brain injury
Author(s) -
Li Yuan,
Lu Bingzheng,
Sheng Longxiang,
Zhu Zhu,
Sun Hongjiaqi,
Zhou Yuwei,
Yang Yang,
Xue Dongdong,
Chen Wenli,
Tian Xuyan,
Du Yun,
Yan Min,
Zhu Wenbo,
Xing Fan,
Li Kai,
Lin Suizhen,
Qiu Pengxin,
Su Xingwen,
Huang Yijun,
Yan Guangmei,
Yin Wei
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14267
Subject(s) - neuroinflammation , microglia , glycolysis , ischemia , penumbra , microbiology and biotechnology , in vivo , hexokinase , gene knockdown , brain ischemia , hypoxia (environmental) , anaerobic glycolysis , biology , chemistry , pharmacology , neuroscience , biochemistry , inflammation , medicine , immunology , enzyme , apoptosis , oxygen , organic chemistry
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 ( HK 2) were essential for microglia‐mediated neuroinflammation under hypoxia. Mechanistically, HK 2 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 HK 2 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 ( MCA o) surgery. We provide novel insights for HK 2 specifically serving as a neuroinflammatory determinant, thus explaining the neurotoxic effect of hyperglycolysis and indicating the possibility of selectively targeting HK 2 as a therapeutic strategy in acute ischemic stroke.