Figure 4.

Metabolic and Epigenetic Pathways involved in IIM: A Comparative Insight into HSPCs vs. Myeloid Cells. The initiation of mechanisms required for inducing innate immune memory depends on the duality of epigenetic and metabolic reprogramming of innate immune cells upon stimulation. During the initial challenge, the recognition of specific ligands by patter recognition receptors triggers a series of intracellular cascades, leading to the upregulation of various metabolic pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and glutaminolysis. Metabolites produced from these processes, like fumarate and acetyl coenzyme A (acetyl-CoA), can activate or inhibit enzymes involved in remodeling the cell's epigenetic landscape, such as the histone demethylase lysine-specific demethylase 5 (KDM5) and histone acetyltransferases. This results in specific changes in the histone methylation and acetylation of genes involved in innate immune responses. This increases the accessibility of DNA to the transcriptional machinery and gene regulatory elements, as well as specific long non-coding RNAs, thereby promoting and facilitating enhanced gene transcription upon secondary stimulation of the cells.