Article (Scientific journals)
Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels.
Cordes, Thekla; Wallace, Martina; MICHELUCCI, Alessandro et al.
2016In The Journal of biological chemistry, 291 (27), p. 14274-84
Peer reviewed
 

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Keywords :
Animals; Cell Line; Hydro-Lyases/physiology; Lipopolysaccharides/pharmacology; Macrophages/drug effects/metabolism; Mice; Succinate Dehydrogenase/antagonists & inhibitors; Succinates/pharmacology; Succinic Acid/metabolism; immunoresponsive gene 1 (Irg1); inflammation; itaconate; macrophage; metabolic regulation; mitochondrial metabolism; mitochondrial respiratory chain complex; succinate; succinate dehydrogenase (SDH)
Abstract :
[en] 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.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Cordes, Thekla
Wallace, Martina
MICHELUCCI, Alessandro ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Divakaruni, Ajit S.
Sapcariu, Sean C.
SOUSA, Carole ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) ; Luxembourg Institute of Health - LIH
Koseki, Haruhiko
Cabrales, Pedro
Murphy, Anne N.
Hiller, Karsten
Metallo, Christian M.
External co-authors :
yes
Language :
English
Title :
Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels.
Publication date :
2016
Journal title :
The Journal of biological chemistry
ISSN :
0021-9258
eISSN :
1083-351X
Volume :
291
Issue :
27
Pages :
14274-84
Peer reviewed :
Peer reviewed
Commentary :
(c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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since 03 September 2018

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