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.
Original language | English |
---|---|
Pages (from-to) | 238-242 |
Number of pages | 6 |
Journal | Nature |
Volume | 496 |
Issue number | 7444 |
DOIs | |
Publication status | Published - 11 Apr 2013 |
Keywords / Materials (for Non-textual outputs)
- RECEPTOR GPR91
- HYPOXIA
- ACTIVATION
- PROTEIN
- CELLS
- GAMMA
- LINKS
- METABOLISM
- INHIBITION
- MECHANISM