title: Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation.
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.
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Vicky
authors.initials: V
authors.lastname: Lampropoulou
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Computer Technologies Department, ITMO University, Saint Petersburg 197101, Russia.
authors.forename: Alexey
authors.initials: A
authors.lastname: Sergushichev
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Bambouskova
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Nair
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; and Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Vincent
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Loginicheva
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Cervantes-Barragan
authors.affiliation: Center for Cardiovascular Research in Department of Medicine, and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA; and John Cochran VA Medical Center, St. Louis, MO 63108, USA.
authors.forename: Xiucui
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Stanley Ching-Cheng
authors.initials: SC
authors.lastname: Huang
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; and Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Takla
authors.initials: T
authors.lastname: Griss
authors.affiliation: Division of Cardiology and Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA; and John Cochran VA Medical Center, St. Louis, MO 63108, USA.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Weinheimer
authors.affiliation: Department of Molecular Microbiology, Washington University at St. Louis, St. Louis, MO 63110, USA.
authors.forename: Shabaana
authors.initials: S
authors.lastname: Khader
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Faculty of Biology, University of Freiburg, and Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pearce
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; and Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
authors.affiliation: Center for Cardiovascular Research in Department of Medicine, and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA; and John Cochran VA Medical Center, St. Louis, MO 63108, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University at St. Louis, St. Louis, MO 63110, USA; Center for Human Immunology and Immunotherapy Programs, Washington University at St. Louis, St. Louis, MO 63110, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Human Immunology and Immunotherapy Programs, Washington University at St. Louis, St. Louis, MO 63110, USA. Electronic address: martyomov@pathology.wustl.edu.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D005260:Female; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013386:Succinates / Q000494:pharmacology*; D019802:Succinic Acid / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D013386:Succinates; D019802:Succinic Acid; D013385:Succinate Dehydrogenase; C005229:itaconic acid