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Succinate Is An Inflammatory Signal That Induces IL-1β Through HIF-1α

G. Tannahill, A. Curtis, J. Adamík, E. Pålsson-McDermott, A. F. McGettrick, G. Goel, C. Frezza, N. Bernard, B. Kelly, N. Foley, L. Zheng, A. Gardet, Z. Tong, S. Jany, S. Corr, M. Haneklaus, B. Caffrey, K. Pierce, S. Walmsley, F. Beasley, E. Cummins, V. Nizet, M. Whyte, C. Taylor, H. Lin, S. Masters, E. Gottlieb, V. Kelly, C. Clish, P. Auron, R. Xavier, L. O’Neill
Published 2013 · Biology, Medicine

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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-1β but not tumour-necrosis factor-α 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 (γ-aminobutyric acid) shunt’ pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β 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-1β production during inflammation.
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Supplementary Information is available in the online version of the paper
designed and did experiments, analysed data and wrote the paper; L.A.J.O. conceived ideas and oversaw the research programme
Author Contributions

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