Metabolic reprogramming
Trained immunity has also been established to involve changes in cell metabolism, as indicted by the different metabolic pathways of two types of activated macrophage, namely the classically activated M1 macrophages and alternatively activated M2 macrophages. Whereas M1 macrophages tend to utilize glycolytic metabolism for energy generation, M2 macrophages are primarily dependent on oxidative phosphorylation for ATP biogenesis35, 36. In this context, Cheng et al.37 have reported that the metabolic basis of trained immunity triggered by theC. albicans cell wall constituent β-glucan is the induction of aerobic glycolysis dependent on an AKT-mammalian target of rapamycin (mTOR)-hypoxia-inducible factor-1α (HIF-1α) pathway. Furthermore, trained human monocytes have been shown to be characterized by high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD+) to nicotinamide adenine dinucleotide (NADH), reflecting a shift in cell metabolism from oxidative phosphorylation to aerobic glycolysis. Similar changes in glucose metabolism have also been observed in BCG-induced trained immunity 38. Such changes in cell metabolism facilitate the rapid conversion of glucose to lactic acid in the cytoplasm, thereby yielding the energy necessary to mount a rapid response to secondary challenge 39. Furthermore, in the case of LPS-induced immunological memory, macrophages have been observed to display strong and transient glycolytic metabolism during the acute response, whereas after the stimulation subsided, the metabolic polarity shifts back to oxidative phosphorylation, and histones in the transcriptional region of the genome are deacetylated by deacetylase-1 and deacetylase-6, thereby establishing the immune tolerance memory of macrophages40. In addition, intermediate metabolites have also been established to be involved in the regulation of macrophage memory. For example, the metabolite mevalonate has been shown to induce trained immunity by activating IGF1-R and mTOR and subsequent histone modifications in inflammatory pathways 41. Furthermore, the tricarboxylic acid cycle (TCA) metabolite fumarate provides a link integrating immune and metabolic circuits to induce the epigenetic reprogramming of monocytes by downregulating KDM5 histone demethylases 42, 43. Additionally, glutamine metabolism has been demonstrated to promote a high accumulation of α-ketoglutarate, and a corresponding elevation in the α-ketoglutarate/succinate ratio was found to be sufficient to regulate H3K27me3 modification and ten-eleven translocation-dependent DNA demethylation, which contribute to the induction of macrophage memory42-44.