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Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha

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  • G. M. Tannahill
  • A. M. Curtis
  • J. Adamik
  • E. M. Palsson-McDermott
  • A. F. McGettrick
  • G. Goel
  • C. Frezza
  • N. J. Bernard
  • B. Kelly
  • N. H. Foley
  • L. Zheng
  • A. Gardet
  • Z. Tong
  • S. S. Jany
  • S. C. Corr
  • M. Haneklaus
  • B. E. Caffrey
  • K. Pierce
  • F. C. Beasley
  • E. Cummins
  • V. Nizet
  • C. T. Taylor
  • H. Lin
  • E. Gottlieb
  • V. P. Kelly
  • C. Clish
  • P. E. Auron
  • R. J. Xavier
  • L. A. J. O'Neill

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    Rights statement: Published in final edited form as: Nature. Apr 11, 2013; 496(7444): 238–242

    Accepted author manuscript, 986 KB, PDF document

http://www.nature.com/nature/journal/v496/n7444/full/nature11986.html
Original languageEnglish
Pages (from-to)238-242
Number of pages6
JournalNature
Volume496
Issue number7444
DOIs
Publication statusPublished - 11 Apr 2013

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.

    Research areas

  • RECEPTOR GPR91, HYPOXIA, ACTIVATION, PROTEIN, CELLS, GAMMA, LINKS, METABOLISM, INHIBITION, MECHANISM

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