Metabolic support of trained immune responses in myeloid cells.

Trained immunity (TI) is defined as a form of innate immune memory characterised by a long-lasting ability to develop enhanced responses to a secondary challenge, whether of the same or a different nature than the initial stimulus. This process is mediated by several established hallmarks, most prominently the existence of activating epigenetic marks and metabolic adaptations. The activating epigenetic marks prime the expression of immune-related genes and are a direct driving force behind the increased cytokine production after secondary stimulation of trained monocytes and macrophages. Training stimuli also induce specific metabolic adaptations, such as the upregulation of glycolysis and lactate production or the activation of glutaminolysis leading to fumarate accumulation, which in turn promotes epigenetic changes. However, the mechanisms linking these epigenetic and metabolic changes to a TI phenotype are varied, and not all stimuli that increase glycolysis promote training, whereas some stimuli such as lipopolysaccharide (LPS) display a non-monotonic induction of TI. In addition to metabolism directly driving epigenetic changes, early gene expression changes can also reshape cell metabolism to promote a trained phenotype. In this review we aim to separate two main types of metabolic rewiring that have not been previously uncoupled. Firstly, those primary metabolic changes occurring during the initial stimulation, which precede TI induction by altering the epigenomic landscape around inflammatory genes. Secondly, those metabolic adaptations arising later as a consequence of the first wave of epigenetic regulation, which support an enhanced functional state of macrophages.