PMID- 25258083
OWN - NLM
STAT- MEDLINE
DCOM- 20141023
LR  - 20220409
IS  - 1095-9203 (Electronic)
IS  - 0036-8075 (Print)
IS  - 0036-8075 (Linking)
VI  - 345
IP  - 6204
DP  - 2014 Sep 26
TI  - mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained 
      immunity.
PG  - 1250684
LID - 10.1126/science.1250684 [doi]
AB  - 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 beta-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-1alpha (hypoxia-inducible factor-1alpha) pathway. Inhibition of Akt, 
      mTOR, or HIF-1alpha 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-1alpha were unable to mount trained immunity against bacterial sepsis. 
      Our results indicate that induction of aerobic glycolysis through an 
      Akt-mTOR-HIF-1alpha pathway represents the metabolic basis of trained immunity.
CI  - Copyright (c) 2014, American Association for the Advancement of Science.
FAU - Cheng, Shih-Chin
AU  - Cheng SC
AD  - Department of Internal Medicine, Radboud University Medical Center, 6525 GA 
      Nijmegen, Netherlands.
FAU - Quintin, Jessica
AU  - Quintin J
AD  - Department of Internal Medicine, Radboud University Medical Center, 6525 GA 
      Nijmegen, Netherlands.
FAU - Cramer, Robert A
AU  - Cramer RA
AD  - Department of Microbiology and Immunology, Geisel School of Medicine at 
      Dartmouth, Hanover, NH 03755, USA.
FAU - Shepardson, Kelly M
AU  - Shepardson KM
AD  - Department of Microbiology and Immunology, Geisel School of Medicine at 
      Dartmouth, Hanover, NH 03755, USA.
FAU - Saeed, Sadia
AU  - Saeed S
AD  - Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen 
      Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, 
      Netherlands.
FAU - Kumar, Vinod
AU  - Kumar V
AD  - Department of Genetics, University of Groningen, University Medical Center 
      Groningen, Groningen, Netherlands.
FAU - Giamarellos-Bourboulis, Evangelos J
AU  - Giamarellos-Bourboulis EJ
AD  - 4th Department of Internal Medicine, University of Athens Medical School, 12462 
      Athens, Greece.
FAU - Martens, Joost H A
AU  - Martens JH
AD  - Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen 
      Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, 
      Netherlands.
FAU - Rao, Nagesha Appukudige
AU  - Rao NA
AD  - Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen 
      Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, 
      Netherlands.
FAU - Aghajanirefah, Ali
AU  - Aghajanirefah A
AD  - Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen 
      Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, 
      Netherlands.
FAU - Manjeri, Ganesh R
AU  - Manjeri GR
AD  - Department of Biochemistry, Faculties of Science and Medicine, Nijmegen Centre 
      for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
FAU - Li, Yang
AU  - Li Y
AD  - Department of Genetics, University of Groningen, University Medical Center 
      Groningen, Groningen, Netherlands.
FAU - Ifrim, Daniela C
AU  - Ifrim DC
AD  - Department of Internal Medicine, Radboud University Medical Center, 6525 GA 
      Nijmegen, Netherlands.
FAU - Arts, Rob J W
AU  - Arts RJ
AD  - Department of Internal Medicine, Radboud University Medical Center, 6525 GA 
      Nijmegen, Netherlands.
FAU - van der Veer, Brian M J W
AU  - van der Veer BM
AD  - Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen 
      Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, 
      Netherlands.
FAU - Deen, Peter M T
AU  - Deen PM
AD  - Department of Physiology, Radboud University Medical Center, 6525 GA Nijmegen, 
      Netherlands.
FAU - Logie, Colin
AU  - Logie C
AD  - Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen 
      Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, 
      Netherlands.
FAU - O'Neill, Luke A
AU  - O'Neill LA
AD  - School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 
      Trinity College Dublin, Dublin 2, Ireland.
FAU - Willems, Peter
AU  - Willems P
AD  - Department of Biochemistry, Faculties of Science and Medicine, Nijmegen Centre 
      for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, Netherlands.
FAU - van de Veerdonk, Frank L
AU  - van de Veerdonk FL
AD  - Department of Internal Medicine, Radboud University Medical Center, 6525 GA 
      Nijmegen, Netherlands.
FAU - van der Meer, Jos W M
AU  - van der Meer JW
AD  - Department of Internal Medicine, Radboud University Medical Center, 6525 GA 
      Nijmegen, Netherlands.
FAU - Ng, Aylwin
AU  - Ng A
AD  - 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.
FAU - Joosten, Leo A B
AU  - Joosten LA
AD  - Department of Internal Medicine, Radboud University Medical Center, 6525 GA 
      Nijmegen, Netherlands.
FAU - Wijmenga, Cisca
AU  - Wijmenga C
AD  - Department of Genetics, University of Groningen, University Medical Center 
      Groningen, Groningen, Netherlands.
FAU - Stunnenberg, Hendrik G
AU  - Stunnenberg HG
AD  - Department of Genetics, University of Groningen, University Medical Center 
      Groningen, Groningen, Netherlands.
FAU - Xavier, Ramnik J
AU  - Xavier RJ
AD  - 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.
FAU - Netea, Mihai G
AU  - Netea MG
AD  - Department of Internal Medicine, Radboud University Medical Center, 6525 GA 
      Nijmegen, Netherlands. mihai.netea@radboudumc.nl.
LA  - eng
SI  - GEO/GSE57206
GR  - 5P30GM103415-03/GM/NIGMS NIH HHS/United States
GR  - P30 DK043351/DK/NIDDK NIH HHS/United States
GR  - P30 GM106394/GM/NIGMS NIH HHS/United States
GR  - DK43351/DK/NIDDK NIH HHS/United States
GR  - P30 GM103415/GM/NIGMS NIH HHS/United States
GR  - 1P30GM106394-01/GM/NIGMS NIH HHS/United States
GR  - 310372/ERC_/European Research Council/International
GR  - DK097485/DK/NIDDK NIH HHS/United States
GR  - R01 DK097485/DK/NIDDK NIH HHS/United States
GR  - R01 AI081838/AI/NIAID NIH HHS/United States
GR  - R01AI81838/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Science
JT  - Science (New York, N.Y.)
JID - 0404511
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (beta-Glucans)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
EIN - Science. 2014 Nov 7;346(6210):aaa1503. van der Meer, Brian M J W [corrected to 
      van der Veer, Brian M J W]
CIN - Nat Rev Immunol. 2014 Nov;14(11):713. PMID: 25301255
MH  - Aerobiosis/immunology
MH  - Animals
MH  - Candida albicans/immunology
MH  - Candidiasis/immunology/metabolism
MH  - Disease Models, Animal
MH  - *Epigenesis, Genetic
MH  - Female
MH  - Glucose/metabolism
MH  - Glycolysis/*immunology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Immunity, Innate/*genetics
MH  - Immunologic Memory/*genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Monocytes/*immunology/metabolism
MH  - Sepsis/genetics/immunology/metabolism
MH  - Staphylococcal Infections/immunology/metabolism
MH  - Staphylococcus aureus
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Transcriptome
MH  - beta-Glucans/immunology
PMC - PMC4226238
MID - NIHMS640144
EDAT- 2014/09/27 06:00
MHDA- 2014/10/24 06:00
PMCR- 2015/03/26
CRDT- 2014/09/27 06:00
PHST- 2014/09/27 06:00 [entrez]
PHST- 2014/09/27 06:00 [pubmed]
PHST- 2014/10/24 06:00 [medline]
PHST- 2015/03/26 00:00 [pmc-release]
AID - 345/6204/1250684 [pii]
AID - 10.1126/science.1250684 [doi]
PST - ppublish
SO  - Science. 2014 Sep 26;345(6204):1250684. doi: 10.1126/science.1250684.