title: Succinate is an inflammatory signal that induces IL-1β through HIF-1α.
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.
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: G M
authors.initials: GM
authors.lastname: Tannahill
authors.forename: A M
authors.initials: AM
authors.lastname: Curtis
authors.forename: J
authors.initials: J
authors.lastname: Adamik
authors.forename: E M
authors.initials: EM
authors.lastname: Palsson-McDermott
authors.forename: A F
authors.initials: AF
authors.lastname: McGettrick
authors.forename: G
authors.initials: G
authors.lastname: Goel
authors.forename: C
authors.initials: C
authors.lastname: Frezza
authors.forename: N J
authors.initials: NJ
authors.lastname: Bernard
authors.forename: B
authors.initials: B
authors.lastname: Kelly
authors.forename: N H
authors.initials: NH
authors.lastname: Foley
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.forename: A
authors.initials: A
authors.lastname: Gardet
authors.forename: Z
authors.initials: Z
authors.lastname: Tong
authors.forename: S S
authors.initials: SS
authors.lastname: Jany
authors.forename: S C
authors.initials: SC
authors.lastname: Corr
authors.forename: M
authors.initials: M
authors.lastname: Haneklaus
authors.forename: B E
authors.initials: BE
authors.lastname: Caffrey
authors.forename: K
authors.initials: K
authors.lastname: Pierce
authors.forename: S
authors.initials: S
authors.lastname: Walmsley
authors.forename: F C
authors.initials: FC
authors.lastname: Beasley
authors.forename: E
authors.initials: E
authors.lastname: Cummins
authors.forename: V
authors.initials: V
authors.lastname: Nizet
authors.forename: M
authors.initials: M
authors.lastname: Whyte
authors.forename: C T
authors.initials: CT
authors.lastname: Taylor
authors.forename: H
authors.initials: H
authors.lastname: Lin
authors.forename: S L
authors.initials: SL
authors.lastname: Masters
authors.forename: E
authors.initials: E
authors.lastname: Gottlieb
authors.forename: V P
authors.initials: VP
authors.lastname: Kelly
authors.forename: C
authors.initials: C
authors.lastname: Clish
authors.forename: P E
authors.initials: PE
authors.lastname: Auron
authors.forename: R J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: L A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002952:Citric Acid Cycle / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D050259:Genes, Mitochondrial / Q000187:drug effects / Q000235:genetics; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D019802:Succinic Acid / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D005973:Glutamine; D005680:gamma-Aminobutyric Acid; D003847:Deoxyglucose; D019802:Succinic Acid
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