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Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha
MCGETTRICK-DILLON, ANNE; CORR, SINEAD; PALSSON, EVA; KELLY, VINCENT; O'NEILL, LUKE
Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1? but not tumour-necrosis factor-? in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (?-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1?, an effect that is inhibited by 2-deoxyglucose, with interleukin-1? as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1? production during inflammation.
Keyword(s): tricarboxylic-acid cycle intermediate succinate; Immunology, Inflammation & Infection
Publication Date:
2013
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Institution: Trinity College Dublin
Citation(s): Tannahill, GM, Curtis, AM, Adamik, J, Palsson-McDermott, EM, McGettrick, AF, Goel, G, Frezza, C, Bernard, NJ, Kelly, B, Foley, NH, Zheng, L, Gardet, A, Tong, Z, Jany, SS, Corr, SC, Haneklaus, M, Caffrey, BE, Pierce, K, Walmsley, S, Beasley, FC, Cummins, E, Nizet, V, Whyte, M, Taylor, CT, Lin, H, Masters, SL, Gottlieb, E, Kelly, VP, Clish, C, Auron, PE, Xavier, RJ, O'Neill, LAJ, Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha, NATURE, 496, 7444, 2013, 238-+
First Indexed: 2015-01-12 05:32:41 Last Updated: 2020-10-30 07:48:17