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

Nature. 2013 Apr 11;496(7444):238-42. doi: 10.1038/nature11986. Epub 2013 Mar 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Citric Acid Cycle / drug effects
  • Deoxyglucose / pharmacology
  • Down-Regulation / drug effects
  • Genes, Mitochondrial / drug effects
  • Genes, Mitochondrial / genetics
  • Glutamine / metabolism
  • Glycolysis / drug effects
  • Glycolysis / genetics
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunity, Innate / drug effects
  • Inflammation / metabolism
  • Interleukin-1beta / biosynthesis*
  • Interleukin-1beta / genetics
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Signal Transduction*
  • Succinic Acid / metabolism*
  • Up-Regulation / drug effects
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-1beta
  • Lipopolysaccharides
  • Glutamine
  • gamma-Aminobutyric Acid
  • Deoxyglucose
  • Succinic Acid