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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aerobiosis / immunology
  • Animals
  • Candida albicans / immunology
  • Candidiasis / immunology
  • Candidiasis / metabolism
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Female
  • Glucose / metabolism
  • Glycolysis / immunology*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunity, Innate / genetics*
  • Immunologic Memory / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Sepsis / genetics
  • Sepsis / immunology
  • Sepsis / metabolism
  • Staphylococcal Infections / immunology
  • Staphylococcal Infections / metabolism
  • Staphylococcus aureus
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcriptome
  • beta-Glucans / immunology

Substances

  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • beta-Glucans
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Glucose

Associated data

  • GEO/GSE57206