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J Biol Chem. 2016 Jul 1;291(27):14274-84. doi: 10.1074/jbc.M115.685792. Epub 2016 May 9.

Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels.

Author information

1
From the Departments of Bioengineering and.
2
the NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 1526 Luxembourg, Luxembourg, the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362 Esch-Belval, Luxembourg, and.
3
Pharmacology and.
4
the Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362 Esch-Belval, Luxembourg, and.
5
the RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
6
From the Departments of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California 92093, cmetallo@ucsd.edu.

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.

KEYWORDS:

immunoresponsive gene 1 (Irg1); inflammation; itaconate; macrophage; metabolic regulation; mitochondrial metabolism; mitochondrial respiratory chain complex; succinate; succinate dehydrogenase (SDH)

PMID:
27189937
PMCID:
PMC4933182
DOI:
10.1074/jbc.M115.685792
[Indexed for MEDLINE]
Free PMC Article

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