The metabolic response to inflammation in astrocytes is regulated by nuclear factor-kappa B signaling.
The metabolic response to inflammation in astrocytes is regulated by nuclear factor-kappa B signaling.
复制标题
星形胶质细胞对炎症的代谢反应受到核因子 kappa B 信号传导的调节。
作者：
Robb JL
炎症和代谢与诱导细胞中代谢变化的炎症刺激内在相关，并且反过来，代谢能力决定细胞炎症反应。虽然在外周免疫细胞中有很好的特点，但对星形胶质细胞中的这些“免疫代谢”反应知之甚少。在这项研究中，我们检验了核因子-κ B（NF-κB）信号转导驱动的星形胶质细胞炎症反应依赖于糖酵解代谢的假设。使用小鼠原代皮质星形胶质细胞培养物，我们评估了暴露于脂多糖（LPS）后细胞代谢的变化，细胞因子ELISA和免疫印迹法用于测量炎症反应。结果表明，星形胶质细胞对促炎刺激的时间上不同的代谢适应：LPS处理3小时增加了糖酵解，但没有改变线粒体代谢，而LPS处理24小时后，我们观察到氧化磷酸化增加，糖酵解能力和葡萄糖摄取减少，部分原因是葡萄糖转运蛋白1表达减少。用IKK-β抑制剂TPCA-1抑制NF-κB信号传导可防止LPS诱导的糖酵解和氧化磷酸化变化。此外，TPCA-1处理改变了糖酵解和氧化磷酸化，与炎症刺激无关，表明NF-κB信号在星形胶质细胞基础代谢调节中的作用。用2-脱氧葡萄糖抑制糖酵解显著减弱了LPS诱导的细胞因子释放和NF-κB磷酸化，表明完整的糖酵解是对LPS的完全炎症反应所必需的。总之，我们的数据表明，星形胶质细胞显示急性LPS刺激的免疫代谢反应，这可能是一个潜在的治疗目标，神经炎症性疾病。
Inflammation and metabolism are intrinsically linked with inflammatory stimuli inducing metabolic changes in cells and, in turn, metabolic capacity determining cellular inflammatory responses. Although well characterized in peripheral immune cells there is comparatively less known about these “immunometabolic” responses in astrocytes. In this study, we tested the hypothesis that the astrocytic inflammatory response driven by nuclear factor‐kappa B (NF‐κB) signaling is dependent on glycolytic metabolism. Using mouse primary cortical astrocyte cultures, we assessed changes in cellular metabolism after exposure to lipopolysaccharide (LPS), with cytokine ELISAs and immunoblotting being used to measure inflammatory responses. Results indicate temporally distinct metabolic adaptations to pro‐inflammatory stimulation in astrocytes: 3 hr LPS treatment increased glycolysis but did not alter mitochondrial metabolism, while following 24 hr of LPS treatment we observed increased oxidative phosphorylation, and decreased glycolytic capacity and glucose uptake, partly due to reduced glucose transporter 1 expression. Inhibition of NF‐κB signaling with the IKK‐beta inhibitor TPCA‐1 prevented the LPS induced changes to glycolysis and oxidative phosphorylation. Furthermore, TPCA‐1 treatment altered both glycolysis and oxidative phosphorylation independently from inflammatory stimulation, indicating a role for NF‐κB signaling in regulation of basal metabolism in astrocytes. Inhibition of glycolysis with 2‐deoxyglucose significantly attenuated LPS‐induced cytokine release and NF‐κB phosphorylation, indicating that intact glycolysis is required for the full inflammatory response to LPS. Together our data indicate that astrocytes display immunometabolic responses to acute LPS stimulation which may represent a potential therapeutic target for neuroinflammatory disorders.