Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha
- Author(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;
- Details
- Publication Year 2013-04-11,Volume 496,Issue #7444,Page 238-242
- Journal Title
- NATURE
- Publication Type
- Journal Article
- Abstract
- Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis(1). Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1 beta but not tumour-necrosis factor-a in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and down-regulation 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 (gamma-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1 alpha, an effect that is inhibited by 2-deoxyglucose, with interleukin-1 beta 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 beta production during inflammation.
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- RECEPTOR GPR91; HYPOXIA; ACTIVATION; PROTEIN; CELLS; GAMMA; LINKS; METABOLISM; INHIBITION; MECHANISM
- Research Division(s)
- Inflammation
- Publisher's Version
- https://doi.org/10.1038/nature11986
- Terms of Use/Rights Notice
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Creation Date: 2013-04-11 12:00:00