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

Abstract

Epigenetic reprogramming of myeloid cells by infection or vaccination, termed trained immunity, confers non-specific protection from secondary infections. We characterized genome-wide transcriptome and histone modification profiles of human monocytes trained with β-glucan and identified induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, lactate production, and NAD+/NADH ratio, reflecting a shift in the metabolism of trained monocytes with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1/Akt/HIF1α pathway. Inhibition of Akt, mTOR, or HIF1α blocked monocyte induction of trained immunity, whereas the AMPK activator metformin inhibited the innate immune response to fungal infection. Finally, mice with a myeloid cell-specific defect in HIF1α were unable to mount trained immunity against bacterial sepsis. In conclusion, Akt/mTOR/HIF1α-dependent induction of aerobic glycolysis represents the metabolic basis of trained immunity.

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

“…It is interesting that glycolysis not only plays an important nonbioenergetic role during immune recall (14,25), but it also is critically required in the context of immune surveillance. Increased glycolytic capacity has recently been proposed as a hallmark of immune-experienced cells ("trained immunity") (26). Mechanistically linking nonbioenergetic aspects of glycolysis to EM CD4 + T cell survival adds an important facet to this concept.…”

Natural killer cell memory in infection, inflammation and cancer

“…Similarly, challenge of mice with CpG-DNA, which engages Toll-like receptor 9 (TLR9), can confer long-term protection against Listeria monocytogenes infection 82 , which could be transferred by a subpopulation of dendritic cells to naive recipient mice 83 . Recent studies have unravelled the cellular processes and dissected genetic and epigenetic differences of naive monocytes and monocytes briefly stimulated with β-glycan (also known as TGFR3) and then rested for an additional 5 days 84,85 . These β-glycan-pretreated monocytes, which were referred to as 'trained' monocytes, exhibited a distinct epigenetic programme that did not require DNA replication.…”

The effects of metformin on gut microbiota and the immune system as research frontiers

“…Although no detailed clinical studies examining influences of metformin on more subtle aspects of immune function have been carried out, laboratory studies [34][35][36][37][38][39][40][41][42][43][44][45] have provided considerable evidence for a variety of immunomodulatory effects.…”

“…While the notion that metformin may influence immune function as a consequence of altering energy metabolism in the many cell lineages that comprise the immune system is straightforward, it is unclear what subpopulations of immune cells are most affected by the drug, and therefore what the net effect on immune function would be in different clinical contexts. Recent results in tumour immunology provide examples of enhanced immune function as a consequence of metformin exposure [36][37][38], while studies in other contexts, including tuberculosis and multiple sclerosis, suggest anti-inflammatory actions [40][41][42][43][44][45].…”

“…However, the precise molecular target of metformin that leads to inhibition of NF-κB remains to be defined. Inhibition of the innate immune response to fungal infection by metformin in an AMPK-dependent manner has been observed in model systems [42], but the clinical relevance of these observations also remains to be determined.…”