Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation

Vicky Lampropoulou, Alexey Sergushichev, Monika Bambouskova, Sharmila Nair, Emma E Vincent, Ekaterina Loginicheva, Luisa Cervantes-Barragan, Xiucui Ma, Stanley Ching-Cheng Huang, Takla Griss, Carla J Weinheimer, Shabaana Khader, Gwendalyn J Randolph, Edward J Pearce, Russell G Jones, Abhinav Diwan, Michael S Diamond, Maxim N Artyomov

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Abstract

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.

Original languageEnglish
Pages (from-to)158-166
Number of pages9
JournalCell Metabolism
Volume24
Issue number1
Early online date30 Jun 2016
DOIs
Publication statusPublished - 12 Jul 2016

Keywords

  • Journal Article

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