Key Role of Histone Modifiers in Coupling Metabolism to Epigenetic Reprogramming Associated with “Trained Immunity” in Innate Immune Cells

Trained immunity refers to an acquired immune memory component of innate immune cells, which respond quickly and robustly to secondary infections. It’s very different from adaptive immunity since it is nonselective and doesn’t depend on gene rearrangement; instead, epigenetic reprogramming acts as a foundation for trained immunity. Microbial or metabolic stimuli lead to epigenetic modifications that are influenced by metabolic pathway flux, resulting in enhanced inflammatory responses upon the secondary challenge. This chapter explores how epigenetic modifiers act as a bridge between metabolic pathway mediators and the proinflammatory response through a “poised” transcriptional state of chromatin that helps maintain a long-lasting epigenetic memory, influencing gene expression programs of innate immunity. We describe how cellular metabolites are not limited to metabolic pathway regulation, but they also influence the development and maintenance of a primed epigenetic landscape and shape inflammatory responses. We also discuss how different histone marks regulate gene expression during trained immunity and how key metabolites have unique roles in the function of histone-modifiers, including a direct role of metabolites in their enzymatic activity. We highlight major trained immunity inducers and how altered metabolite levels and epigenetic reprogramming integrate peripheral and central trained immunity for a long-lasting response. Finally, we analyze the pathological significance of trained immunity and how its protective capabilities against certain infections can result in maladaptive inflammation, particularly relevant to metabolic diseases, and we propose that a better understanding of epigenetic and metabolic networks during trained immunity has therapeutic potential relevant to immunological and metabolic disorders.