期刊
NATURE
卷 496, 期 7444, 页码 238-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11986
关键词
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资金
- European Research Council
- Science Foundation Ireland
- Health Research Board
- European Union FP7 programme 'TIMER'
- Wellcome Trust
- National Institutes of Health
- Helmsley Trust
- Nestle Research Centre
- VESKI
- Duquesne University Hunkele Dreaded Disease Award
- Interleukin Foundation
- National Health and Medical Research Council
- Medical Research Council [MC_UP_1101/3] Funding Source: researchfish
- MRC [MC_UP_1101/3] Funding Source: UKRI
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.
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