FIG 2.

Intertwist of epigenetics and metabolism in trained immunity. Upon recognition of specific ligands by pattern recognition receptors, intracellular pathways are induced that lead to the upregulation of several metabolic pathways, including glycolysis, glutaminolysis, and cholesterol synthesis. Levels of certain metabolites—citrate and fumarate—are increased and influence epigenetic enzymes, resulting in histone marks associated with trained immunity. In addition, acetyl coenzyme A (acetyl-CoA) is converted into mevalonate, which creates an amplification loop by activating insulin-like growth factor 1 receptor (IGF1R). Long noncoding RNAs are able to bind histone methyltransferase complexes. They guide these complexes to genes and facilitate accumulation of histone 3 lysine 4 trimethylation (H3K4me3) marks. HIF1α, hypoxia-inducible factor 1 alpha; mTOR, mechanistic target of rapamycin; TCA cycle, tricarboxylic acid cycle.