Succinate is an inflammatory signal that induces IL-1β through HIF-1α

Succinate is identified as a metabolite in innate immune signalling, which leads to enhanced interleukin-1β production during inflammation. Succinate is an innate immunity signal The bacterial endotoxin lipopolysaccharide activates macrophages, as part of the innate immunity response, by inducing a...

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Published in:Nature (London) Vol. 496; no. 7444; pp. 238 - 242
Main 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., O’Neill, L. A. J.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 11.04.2013
Nature Publishing Group
Subjects:
631/45/320
Animals
Bone Marrow Cells - cytology
Citric Acid Cycle - drug effects
Deoxyglucose - pharmacology
Down-Regulation - drug effects
gamma-Aminobutyric Acid - metabolism
Genes, Mitochondrial - drug effects
Genes, Mitochondrial - genetics
Glutamine - metabolism
Glycolysis - drug effects
Glycolysis - genetics
Health aspects
Humanities and Social Sciences
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Immunity, Innate - drug effects
Inflammation
Inflammation - metabolism
Interleukin-1beta - biosynthesis
Interleukin-1beta - genetics
Interleukins
letter
Lipopolysaccharides - pharmacology
Macrophages
Macrophages - cytology
Macrophages - drug effects
Macrophages - metabolism
Mice
multidisciplinary
Physiological aspects
Science
Signal Transduction
Succinates
Succinic Acid - metabolism
Up-Regulation - drug effects
ISSN:0028-0836, 1476-4687, 1476-4687
Online Access:Get full text
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Summary:Succinate is identified as a metabolite in innate immune signalling, which leads to enhanced interleukin-1β production during inflammation. Succinate is an innate immunity signal The bacterial endotoxin lipopolysaccharide activates macrophages, as part of the innate immunity response, by inducing a shift from oxidative to glycolytic metabolism. Gillian Tannahill et al . show here that lipopolysaccharide increases levels of the tricarboxylic acid cycle intermediate succinate in macrophages through a metabolic process not previously reported in macrophages, the 'GABA shunt'. Succinate in turn drives the key pro-inflammatory cytokine interleukin-1β. 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-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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ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/nature11986