mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity.
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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
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Journal | Science
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Volume | 345
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Issue | 6204
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Pages | 1250684
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Date Published | 2014 Sep 26
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ISSN | 1095-9203
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URL | |
DOI | 10.1126/science.1250684
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PubMed ID | 25258083
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PubMed Central ID | PMC4226238
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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
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