TY - JOUR
T1 - Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation
AU - Lampropoulou, Vicky
AU - Sergushichev, Alexey
AU - Bambouskova, Monika
AU - Nair, Sharmila
AU - Vincent, Emma E.
AU - Loginicheva, Ekaterina
AU - Cervantes-Barragan, Luisa
AU - Ma, Xiucui
AU - Huang, Stanley Ching Cheng
AU - Griss, Takla
AU - Weinheimer, Carla J.
AU - Khader, Shabaana
AU - Randolph, Gwendalyn J.
AU - Pearce, Edward J.
AU - Jones, Russell G.
AU - Diwan, Abhinav
AU - Diamond, Michael S.
AU - Artyomov, Maxim N.
N1 - Funding Information:
National Institutes of Health (NIH) grant R01 AI104972 (M.S.D.) supported this study. S.N. was supported by a DFG fellowship. The Irg1 −/− targeting allele and ESCs were created by the Mouse Biology Program ( https://www.mousebiology.org/ ) at the University of California Davis. The ESCs were generated by the trans-NIH Knock-Out Mouse Project (KOMP) and obtained from the KOMP Repository ( https://www.komp.org/ ). NIH grants to Velocigene at Regeneron Inc. (U01HG004085) and the CSD Consortium (U01HG004080) funded the generation of gene-targeted vectors and ESCs for over 8,500 genes in the KOMP Program and archived and distributed by the KOMP Repository at UC Davis and CHORI (U42RR024244). We acknowledge technical assistance from the GCRC Metabolomics Core Facility at McGill University. E.E.V. and R.G.J. were supported by grants from the Canadian Institutes for Health Research (CIHR MOP-142259 to R.G.J.). A.D. was supported by grants from NIH (HL107594) and Department of Veterans Affairs (1I01BX001969). A.S. was supported by a grant from the Government of the Russian Federation (074-U01).
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/7/12
Y1 - 2016/7/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84978468846&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2016.06.004
DO - 10.1016/j.cmet.2016.06.004
M3 - Article
C2 - 27374498
AN - SCOPUS:84978468846
SN - 1550-4131
VL - 24
SP - 158
EP - 166
JO - Cell Metabolism
JF - Cell Metabolism
IS - 1
ER -