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Science. 2014 Sep 26;345(6204):1250684. doi: 10.1126/science.1250684.

mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity.

Author information

1
Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
2
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
3
Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
4
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
5
4th Department of Internal Medicine, University of Athens Medical School, 12462 Athens, Greece.
6
Department of Biochemistry, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
7
Department of Physiology, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
8
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
9
Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA 02114, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
10
Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. mihai.netea@radboudumc.nl.

Erratum in

  • Science. 2014 Nov 7;346(6210):aaa1503. van der Meer, Brian M J W [corrected to van der Veer, Brian M J W].

Abstract

Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent β-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD(+)) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1α (hypoxia-inducible factor-1α) pathway. Inhibition of Akt, mTOR, or HIF-1α blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1α were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1α pathway represents the metabolic basis of trained immunity.

Comment in

PMID:
25258083
PMCID:
PMC4226238
DOI:
10.1126/science.1250684
[Indexed for MEDLINE]
Free PMC Article

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