mTOR-mediated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP
mTOR-mediated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP
复制标题
mTOR 介导的代谢重编程塑造了响应脂多糖和 ATP 的不同小胶质细胞功能
DOI：
10.1002/glia.23760
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发表时间：
2019-12-03
期刊：
影响因子：
6.2
通讯作者：
Gao, Zhihua
中科院分区：
文献类型：
--
作者：
Hu, Yaling;Mai, Weihao;Gao, Zhihua
小胶质细胞不断地调查大脑微环境，并迅速采取不同的表型来应对环境刺激。这种动态功能需要独特的新陈代谢和生物能量学。然而，人们对小胶质细胞的基本代谢以及代谢变化如何调节小胶质细胞功能知之甚少。在这里，我们发现小胶质细胞的激活伴随着葡萄糖和脂质代谢相关基因的广泛转录变化。通过代谢通量测定，我们发现LPS（病原体相关分子模式（PAMP）的原型）在原代培养的小胶质细胞中显着增强糖酵解，但抑制氧化磷酸化（OXPHOS）。相比之下，ATP（一种已知的损伤相关分子模式（DAMP），可触发小胶质细胞的无菌激活）促进糖酵解和 OXPHOS。重要的是，LPS 和 ATP 均激活雷帕霉素 (mTOR) 途径的机械靶点并增强细胞内活性氧 (ROS)。在两种情况下，抑制 mTOR 活性都会抑制糖酵解和 ROS 产生，但对 OXPHOS 产生不同的影响：它减弱 ATP 诱导的 OXPHOS 升高，但对 LPS 诱导的 OXPHOS 抑制没有影响。此外，抑制 mTOR 或糖酵解可减少小胶质细胞中 LPS 诱导的促炎细胞因子、ATP 诱导的肿瘤坏死因子-α (TNF-α) 和脑源性神经营养因子 (BDNF) 的产生。我们的研究揭示了 mTOR 在小胶质细胞代谢编程调节中的关键作用，以塑造其在不同状态下的独特功能，并揭示了靶向代谢在多种疾病中干扰小胶质细胞介导的神经炎症的潜在应用。
Microglia constantly survey the brain microenvironment and rapidly adopt different phenotypes in response to environmental stimuli. Such dynamic functions require a unique metabolism and bioenergetics. However, little is known about the basic metabolism of microglia and how metabolic changes regulate microglia function. Here, we uncover that microglia activation is accompanied by extensive transcriptional changes in glucose and lipid metabolism-related genes. Using metabolic flux assays, we found that LPS, a prototype of the pathogen-associated molecular patterns (PAMPs), significantly enhanced glycolysis but suppressed oxidative phosphorylation (OXPHOS) in primary cultured microglia. By contrast, ATP, a known damage-associated molecular pattern (DAMPs) that triggers sterile activation of microglia, boosted both glycolysis and OXPHOS. Importantly, both LPS and ATP activated the mechanistic target of rapamycin (mTOR) pathway and enhanced the intracellular reactive oxygen species (ROS). Inhibition of mTOR activity suppressed glycolysis and ROS production in both conditions but exerted different effects on OXPHOS: it attenuated the ATP-induced elevation of OXPHOS, yet had no impact on the LPS-induced suppression of OXPHOS. Further, inhibition of mTOR or glycolysis decreased production of LPS-induced proinflammatory cytokines and ATP-induced tumor necrosis factor-alpha (TNF-alpha) and brain derived neurotrophic factor (BDNF) in microglia. Our study reveals a critical role for mTOR in the regulation of metabolic programming of microglia to shape their distinct functions under different states and shed light on the potential application of targeting metabolism to interfere with microglia-mediated neuroinflammation in multiple disorders.