mTOR- and HIF-1[alpha]-mediated aerobic glycolysis as metabolic basis for trained immunity

• Published in: Science (American Association for the Advancement of Science) Vol. 345; no. 6204; p. 1250684
• Main Authors: Shih-Chin, Cheng, Quintin, Jessica, Cramer, Robert A, Shepardson, Kelly M, Saeed, Sadia, Kumar, Vinod, Giamarellos-Bourboulis, Evangelos J, Martens, Joost H A, Rao, Nagesha Appukudige, Aghajanirefah, Ali, Manjeri, Ganesh R, Yang, Li, Ifrim, Daniela C, Arts, Rob J W
• Format: Journal Article
• Language: English
• Published: Washington The American Association for the Advancement of Science 26.09.2014; American Association for the Advancement of Science (AAAS)
• Subjects: Aerobiosis; Animals; beta-Glucans; Candida albicans; Candidiasis; Disease Models, Animal; Energy; Epigenesis, Genetic; Female; Glucose; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immune system; Immunity, Innate; Immunologic Memory; Immunology; Individualized Instruction; Innate immunity; Life Sciences; Logical Thinking; Male; Metabolism; Mice; Mice, Inbred C57BL; Microbiology and Parasitology; Monocytes; Mycology; Sepsis; Staphylococcal Infections; Staphylococcus aureus; TOR Serine-Threonine Kinases; Transcriptome; Transcripts (Written Records)
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1250684

Introduction Trained immunity refers to the memory characteristics of the innate immune system. Memory traits of innate immunity have been reported in plants and invertebrates, as well as in mice lacking functional T and B cells that are protected against secondary infections after exposure to certain infections or vaccinations. The underlying mechanism of trained immunity is represented by epigenetic programming through histone modifications, leading to stronger gene transcription upon restimulation. However, the specific cellular processes that mediate trained immunity in monocytes or macrophages are poorly understood. Aerobic glycolysis as metabolic basis for trained immunity. In naïve macrophages during aerobic conditions, glucose metabolism is mainly geared toward oxidative phosphorylation providing adenosine triphosphate (ATP) as the energy source. In contrast, long-term functional reprogramming during trained immunity requires a metabolic shift toward aerobic glycolysis and is induced through a dec tin-1-Akt-mTOR-HIF-1α pathway. Methods We studied a model of trained immunity, induced by the β-glucan component of Candida albicans, that was previously shown to induce nonspecific protection against both infections and malignancies. Genome-wide transcriptome and histone modification profiles were performed and pathway analysis was applied to identify the cellular processes induced during monocyte training. Biological validations were performed in human primary monocytes and in two experimental models in vivo. Results In addition to immune signaling pathways, glycolysis genes were strongly upregulated in terms of histone modification profiling, and this was validated by RNA sequencing of cells from β-glucan-treated mice. The biochemical characterizations of the β-glucan-trained monocytes revealed elevated aerobic glycolysis with reduced basal respiration rate, increased glucose consumption and lactate production, and higher intracellular ratio of nicotinamide adenine dinucleotide (NAD+) to its reduced form (NADH). The dectin-1-Akt-mTOR-HIF-1α pathway (mTOR, mammalian target of rapamycin; HIF-1α, hypoxia-inducible factor-1α) was responsible for the metabolic shift induced by β-glucan. Trained immunity was completely abrogated in monocytes from dectin-1-deficient patients. Blocking of the mTOR-HIF-1α pathway by chemical inhibitors inhibited trained immunity. Mice receiving metformin, an adenosine monophosphate-activated protein kinase (AMPK) activator that subsequently inhibits mTOR, lost the trained immunity-induced protection against lethal C. albicans infection. The role of the mTOR-HIF-1α pathway for β-glucan-induced innate immune memory was further validated in myeloid-specific HIF-1α knockout (mHIF-1α KO) mice that, unlike wild-type mice, were not protected against Staphylococcus aureus sepsis. Discussion The shift of central glucose metabolism from oxidative phosphorylation to aerobic glycolysis (the "Warburg effect") meets the spiked need for energy and biological building blocks for rapid proliferation during carcinogenesis or clonal expansion in activated lymphocytes. We found that an elevated glycolysis is the metabolic basis for trained immunity as well, providing the energy and metabolic substrates for the increased activation of trained immune cells. The identification of glycolysis as a fundamental process in trained immunity further highlights a key regulatory role for metabolism in innate host defense and defines a potential therapeutic target in both infectious and inflammatory diseases. To determine the epigenetic mechanisms that direct blood cells to develop into the many components of our immune system, the BLUEPRINT consortium examined the regulation of DNA and RNA transcription to dissect the molecular traits that govern blood cell differentiation. By inducing immune responses, Saeed et al. document the epigenetic changes in the genome that underlie immune cell differentiation. Cheng et al. demonstrate that trained monocytes are highly dependent on the breakdown of sugars in the presence of oxygen, which allows cells to produce the energy needed to mount an immune response. Chen et al. examine RNA transcripts and find that specific cell lineages use RNA transcripts of different length and composition (isoforms) to form proteins. Together, the studies reveal how epigenetic effects can drive the development of blood cells involved in the immune system. Science, this issue 10.1126/science.1251086, 10.1126/science.1250684, 10.1126/science.1251033 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.