title: Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels.
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.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92093.
authors.forename: Thekla
authors.initials: T
authors.lastname: Cordes
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92093.
authors.forename: Martina
authors.initials: M
authors.lastname: Wallace
authors.affiliation: NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 1526 Luxembourg, Luxembourg,; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362 Esch-Belval, Luxembourg.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Michelucci
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, California 92093.
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Divakaruni
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362 Esch-Belval, Luxembourg.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Sapcariu
authors.affiliation: NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 1526 Luxembourg, Luxembourg,; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362 Esch-Belval, Luxembourg.
authors.forename: Carole
authors.initials: C
authors.lastname: Sousa
authors.affiliation: RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92093.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, California 92093.
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362 Esch-Belval, Luxembourg.
authors.forename: Karsten
authors.initials: K
authors.lastname: Hiller
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92093; Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California 92093,. Electronic address: cmetallo@ucsd.edu.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
mesh_terms: D000818:Animals; D002460:Cell Line; D006836:Hydro-Lyases / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*; D013386:Succinates / Q000494:pharmacology*; D019802:Succinic Acid / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D013386:Succinates; D019802:Succinic Acid; D013385:Succinate Dehydrogenase; D006836:Hydro-Lyases; C487648:Acod1 protein, mouse; C005229:itaconic acid
keywords: immunoresponsive gene 1 (Irg1); inflammation; itaconate; macrophage; metabolic regulation; mitochondrial metabolism; mitochondrial respiratory chain complex; succinate; succinate dehydrogenase (SDH)