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Abstract

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis1. 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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Change history

  • 10 April 2013

    The product code for the anti-HIF-1α antibody was corrected.

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Acknowledgements

We thank the European Research Council, Science Foundation Ireland, the Health Research Board, European Union FP7 programme ‘TIMER’, Wellcome Trust, National Institutes of Health, Helmsley Trust, Nestle Research Centre, VESKI, The Duquesne University Hunkele Dreaded Disease Award, The Interleukin Foundation and the National Health and Medical Research Council for funding. We also thank R. Thompson for assistance with Hif1a−/− mice and M. Murphy for discussions.

Author information

Author notes

    • P. E. Auron
    •  & R. J. Xavier

    These authors contributed equally to this work.

Affiliations

  1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland

    • G. M. Tannahill
    • , A. M. Curtis
    • , E. M. Palsson-McDermott
    • , A. F. McGettrick
    • , N. J. Bernard
    • , B. Kelly
    • , N. H. Foley
    • , S. S. Jany
    • , S. C. Corr
    • , M. Haneklaus
    • , V. P. Kelly
    •  & L. A. J. O’Neill
  2. Department of Biological Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA

    • J. Adamik
    •  & P. E. Auron
  3. Centre for Computational and Integrative Biology, Massachusetts General Hospital, Richard B. Simches Research Center, Boston, Massachusetts 02114, USA

    • G. Goel
    •  & R. J. Xavier
  4. Apoptosis and Tumour Physiology Laboratory, The Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, UK

    • C. Frezza
    • , L. Zheng
    •  & E. Gottlieb
  5. Medical Research Council Cancer Cell Unit Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0X2, UK

    • C. Frezza
    •  & R. J. Xavier
  6. The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • A. Gardet
    • , K. Pierce
    •  & C. Clish
  7. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA

    • Z. Tong
    •  & H. Lin
  8. Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland

    • B. E. Caffrey
  9. Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, UK

    • S. Walmsley
    •  & M. Whyte
  10. V. Nizet Laboratory, Division of Pediatrics, Centre for Neural Circuits and Behaviour, University of California, La Jolla, California 92093-0687, USA

    • F. C. Beasley
    •  & V. Nizet
  11. Conway Institute, University College Dublin, Dublin 4, Ireland

    • E. Cummins
    •  & C. T. Taylor
  12. Inflammation Division, Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3052, Australia

    • S. L. Masters

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Contributions

G.M.T. designed and did experiments, analysed data and wrote the paper; L.A.J.O. conceived ideas and oversaw the research programme; A.M.C, E.M.P., A.F.M. and J.A. designed and did experiments and analysed data; C.F., N.J.B., B.K., N.H.F., L.Z., A.G., Z.T., S.S.J., S.C.C., S.W., K.P. and F.C.B did experiments; G.G., R.J.X., C.C., M.H. and B.E.C. performed bioinformatic analysis; E.C., V.N., M.W., C.T.T., H.L., S.L.M., E.G., V.K. and C.C., provided advice and reagents; P.E.A. and R.J.X. conceived ideas and oversaw a portion of the work.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to L. A. J. O’Neill.

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DOI

https://doi.org/10.1038/nature11986

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