Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels

Thekla Cordes, Martina Wallace, Alessandro Michelucci, Ajit S. Divakaruni, Sean C. Sapcariu, Carole Sousa, Haruhiko Koseki, Pedro Cabrales, Anne N. Murphy, Karsten Hiller, Christian M. Metallo*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

247 Citations (Scopus)

Abstract

Metabolic reprogramming is emerging as a hallmark of the innate immune response, and the dynamic control of metabolites such as succinate serves to facilitate the execution of inflammatory responses in macrophages and other immune cells. Immunoresponsive gene 1 (Irg1) expression is induced by inflammatory stimuli, and its enzyme product cis-aconitate decarboxylase catalyzes the production of itaconate from the tricarboxylic acid cycle. Here we identify an immunometabolic regulatory pathway that links Irg1 and itaconate production to the succinate accumulation that occurs in the context of innate immune responses. Itaconate levels and Irg1 expression correlate strongly with succinate during LPS exposure in macrophages and non-immune cells. We demonstrate that itaconate acts as an endogenous succinate dehydrogenase inhibitor to cause succinate accumulation. Loss of itaconate production in activated macrophages from Irg1 - /- mice decreases the accumulation of succinate in response to LPS exposure. This metabolic network links the innate immune response and tricarboxylic acid metabolism to function of the electron transport chain.

Original languageEnglish
Pages (from-to)14274-14284
Number of pages11
JournalJournal of Biological Chemistry
Volume291
Issue number27
DOIs
Publication statusPublished - 1 Jul 2016

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