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Cell Metab. 2016 Jul 12;24(1):158-66. doi: 10.1016/j.cmet.2016.06.004. Epub 2016 Jun 30.

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

Author information

1
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Computer Technologies Department, ITMO University, Saint Petersburg 197101, Russia.
3
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; and Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
5
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.
6
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.
7
Department of Molecular Microbiology, Washington University at St. Louis, St. Louis, MO 63110, USA.
8
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.
9
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.
10
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.

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.

PMID:
27374498
PMCID:
PMC5108454
DOI:
10.1016/j.cmet.2016.06.004
[Indexed for MEDLINE]
Free PMC Article

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