Hexokinase 2-dependent hyperglycolysis driving microglial activation contributes to ischemic brain injury
Hexokinase 2-dependent hyperglycolysis driving microglial activation contributes to ischemic brain injury
复制标题
己糖激酶 2 依赖性高糖酵解驱动的小胶质细胞活化导致缺血性脑损伤。
DOI：
10.1111/jnc.14267
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发表时间：
2018-01-01
影响因子：
4.7
通讯作者：
Yin, Wei
中科院分区：
文献类型：
--
作者：
Li, Yuan;Lu, Bingzheng;Yin, Wei
在临床和实验研究中发现，脑缺血时半暗带区域出现的高糖酵解现象，因乳酸积累和活性氧过度生成，对组织存活有害。最近，越来越多的证据表明，糖酵解重编程和诱导产生的代谢酶能够推动外周免疫细胞的激活。然而，对于缺血期间高糖酵解在神经炎症中可能发挥的作用及具体细节，我们了解得还相对较少。在此，我们研究了过度激活的糖酵解是否会激活小胶质细胞，并在体外和体内确定了神经炎症反应的关键调节因子。通过BV2细胞和原代小胶质细胞培养，我们发现高糖酵解以及关键糖酵解酶己糖激酶2（HK2）的诱导表达，对于缺氧条件下小胶质细胞介导的神经炎症至关重要。从机制上讲，HK2上调会导致乙酰辅酶A积累，进而引发白细胞介素（IL）-1β的组蛋白乙酰化和转录激活。在接受短暂大脑中动脉闭塞（MCAo）手术的雄性Sprague-Dawley大鼠体内，抑制HK2并选择性敲低其表达，可通过抑制小胶质细胞激活和IL-1β生成，显著减轻缺血性脑损伤。我们为HK2特异性作为神经炎症决定因素提供了新的见解，从而解释了高糖酵解的神经毒性作用，并表明了选择性靶向HK2作为急性缺血性中风治疗策略的可能性。
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)-1b. The inhibition and selective knockdown of HK2 in vivo significantly protected against ischemic brain injury by suppressing microglial activation and IL-1b 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.