巨噬细胞
效应器
炎症
生物
调节器
细胞因子
体内
代谢途径
生物化学
新陈代谢
琥珀酸脱氢酶
体外
细胞生物学
线粒体
柠檬酸循环
免疫学
生物技术
基因
作者
Vicky Lampropoulou,Alexey Sergushichev,Monika Bambousková,Sharmila Nair,Emma E. Vincent,Ekaterina Loginicheva,Luisa Cervantes-Barragán,Xiucui Ma,Stanley Ching-Cheng Huang,Takla Griss,Carla J. Weinheimer,Shabaana A. Khader,Gwendalyn J. Randolph,Edward J. Pearce,Russell G. Jones,Abhinav Diwan,Michael S. Diamond,Maxim N. Artyomov
标识
DOI:10.1016/j.cmet.2016.06.004
摘要
Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1β-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1(-/-) mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.
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