title: mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity.
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.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Shih-Chin
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Quintin
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cramer
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Shepardson
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Sadia
authors.initials: S
authors.lastname: Saeed
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: 4th Department of Internal Medicine, University of Athens Medical School, 12462 Athens, Greece.
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Martens
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Nagesha Appukudige
authors.initials: NA
authors.lastname: Rao
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Ali
authors.initials: A
authors.lastname: Aghajanirefah
authors.affiliation: Department of Biochemistry, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Ganesh R
authors.initials: GR
authors.lastname: Manjeri
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Ifrim
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Rob J W
authors.initials: RJ
authors.lastname: Arts
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Brian M J W
authors.initials: BM
authors.lastname: van der Veer
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Brian M J W
authors.initials: BM
authors.lastname: van der Meer
authors.affiliation: Department of Physiology, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Peter M T
authors.initials: PM
authors.lastname: Deen
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Colin
authors.initials: C
authors.lastname: Logie
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Luke A
authors.initials: LA
authors.lastname: O'Neill
authors.affiliation: Department of Biochemistry, Faculties of Science and Medicine, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Willems
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.affiliation: 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.
authors.forename: Aylwin
authors.initials: A
authors.lastname: Ng
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: 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.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. mihai.netea@radboudumc.nl.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000332:Aerobiosis / Q000276:immunology; D000818:Animals; D002176:Candida albicans / Q000276:immunology; D002177:Candidiasis / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000276:immunology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000235:genetics*; D007156:Immunologic Memory / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013203:Staphylococcal Infections / Q000276:immunology / Q000378:metabolism; D013211:Staphylococcus aureus; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D047071:beta-Glucans / Q000276:immunology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047071:beta-Glucans; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D005947:Glucose