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

GM Tannahill, AM Curtis, J Adamik… - Nature, 2013 - nature.com
GM Tannahill, AM Curtis, J Adamik, EM Palsson-McDermott, AF McGettrick, G Goel
Nature, 2013nature.com
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 …
Abstract
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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