Tannahill, G.M. et al. (2013) Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature, 496(7444), pp. 238-242. (doi: 10.1038/nature11986)
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Abstract
Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis1. 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.
Item Type: | Articles (Letter) |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Frezza, Mr Christian and Zheng, Mr Liang and Gottlieb, Professor Eyal |
Authors: | Tannahill, G.M., Curtis, A.M., Adamik, J., Palsson-McDermott, E.M., McGettrick, A.F., Goel, G., Frezza, C., Bernard, N.J., Kelly, B., Foley, N.H., Zheng, L., Gardet, A., Tong, Z., Jany, S.S., Corr, S.C., Haneklaus, M., Caffrey, B.E., Pierce, K., Walmsley, S., Beasley, F.C., Cummins, E., Nizet, V., Whyte, M., Taylor, C.T., Lin, H., Masters, S.L., Gottlieb, E., Kelly, V.P., Clish, C., Auron, P.E., Xavier, R.J., and O’Neill, L.A.J. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
Journal Name: | Nature |
ISSN: | 0028-0836 |
ISSN (Online): | 1476-4687 |
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