Dataset Information


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 mechanism 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 downstream pro-inflammatory IL-1β-HIF1a 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 via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. 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, changes in 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. Experiment 1: mature WT BMDM were treated for 12h with 0.25 mM dimethyl itaconate (DI) or vehicle (Unst) and then stimulated with LPS (E. coli 0111:B4; 100 ng/ml, 4h) (DI+LPS; LPS); Experiment 2: mature Irg1-/- BMDM were stimulated with LPS (E. coli 0111:B4; 100 ng/ml) and murine recombinant IFNg (50 ng/ml) for 24h.

ORGANISM(S): Mus musculus

SUBMITTER: Maxim Artyomov 

PROVIDER: E-GEOD-82043 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

Similar Datasets

2014-05-30 | E-GEOD-53053 | biostudies-arrayexpress
2010-10-01 | E-GEOD-21548 | biostudies-arrayexpress
2013-12-06 | E-GEOD-47783 | biostudies-arrayexpress
2016-07-01 | GSE82043 | GEO
2010-10-23 | E-GEOD-24832 | biostudies-arrayexpress
2010-10-23 | E-GEOD-24834 | biostudies-arrayexpress
2012-06-27 | E-GEOD-38977 | biostudies-arrayexpress
2009-12-21 | E-GEOD-15610 | biostudies-arrayexpress
2012-03-23 | E-GEOD-32359 | biostudies-arrayexpress
2014-06-03 | E-GEOD-48338 | biostudies-arrayexpress