Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation.
Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation.
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Itaconate连接琥珀酸脱氢酶与巨噬细胞代谢重塑和调节炎症的联系。
DOI：
10.1016/j.cmet.2016.06.004
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发表时间：
2016-07-12
期刊：
影响因子：
29
通讯作者：
Artyomov MN
中科院分区：
文献类型：
--
作者：
Lampropoulou V;Sergushichev A;Bambouskova M;Nair S;Vincent EE;Loginicheva E;Cervantes-Barragan L;Ma X;Huang SC;Griss T;Weinheimer CJ;Khader S;Randolph GJ;Pearce EJ;Jones RG;Diwan A;Diamond MS;Artyomov MN
三羧酸(TCA)循环的重塑是伴随炎性巨噬细胞活化的代谢适应。在这个过程中，内源性代谢物可以发挥调节作用，调控炎症反应的特定方面，如最近显示的琥珀酸，它调节促炎IL-1β-HIF-1α轴。衣康酸是活化巨噬细胞中诱导作用最强的代谢物之一，但其功能意义尚不清楚。在这里，我们表明衣康酸通过抑制琥珀酸脱氢酶介导的琥珀酸氧化来调节巨噬细胞的代谢和效应器功能。通过这一作用，衣康酸在体外和体内给药时，在巨噬细胞激活和缺血再灌注损伤期间发挥抗炎作用。利用新生的缺乏产生衣康酸能力的irg1−/−小鼠，我们证明了内源性衣康酸在巨噬细胞激活过程中调节琥珀酸水平和功能、线粒体呼吸和炎性细胞因子的产生。这些研究强调衣康酸是炎性巨噬细胞全球代谢重组和效应器功能的主要生理调节因子。巨噬细胞的激活伴随着TCA循环的重塑，导致内源性代谢产物兼职作为炎症反应的调节介质。Lampropulou等人。研究衣康酸在激活的巨噬细胞中的作用，发现衣康酸调节琥珀酸水平、线粒体呼吸和细胞因子的产生。
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. Macrophage activation is accompanied by TCA cycle remodeling, resulting in endogenous metabolites moonlighting as regulatory mediators of the inflammatory response. Lampropoulou et al. investigate the role of itaconate, one of the most highly induced metabolites in activated macrophages, and show that itaconate regulates succinate levels, mitochondrial respiration, and cytokine production.
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影响因子：
44.1
作者：
通讯作者：
--
影响因子：
6.7
作者：
Naujoks J;Tabeling C;Dill BD;Hoffmann C;Brown AS;Kunze M;Kempa S;Peter A;Mollenkopf HJ;Dorhoi A;Kershaw O;Gruber AD;Sander LE;Witzenrath M;Herold S;Nerlich A;Hocke AC;van Driel I;Suttorp N;Bedoui S;Hilbi H;Trost M;Opitz B
通讯作者：
Opitz B
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
16
作者：
Vincent, Emma E.;Sergushichev, Alexey;Jones, Russell G.
通讯作者：
Jones, Russell G.
影响因子：
5.8
作者：
Jensen, Paul A.;Papin, Jason A.
通讯作者：
Papin, Jason A.