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.