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

Science
Authors
Keywords
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.

Year of Publication
2014
Journal
Science
Volume
345
Issue
6204
Pages
1250684
Date Published
2014 Sep 26
ISSN
1095-9203
URL
DOI
10.1126/science.1250684
PubMed ID
25258083
PubMed Central ID
PMC4226238
Links
Grant list
5P30GM103415-03 / GM / NIGMS NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
P30 GM106394 / GM / NIGMS NIH HHS / United States
R01 AI081838 / AI / NIAID NIH HHS / United States
R01AI81838 / AI / NIAID NIH HHS / United States
DK43351 / DK / NIDDK NIH HHS / United States
P30 GM103415 / GM / NIGMS NIH HHS / United States
1P30GM106394-01 / GM / NIGMS NIH HHS / United States
DK097485 / DK / NIDDK NIH HHS / United States
R01 DK097485 / DK / NIDDK NIH HHS / United States