Fig. 1

Mechanisms at the cellular and systemic level. Activation of the innate immune system can result in mild responsiveness, while it leads to enhanced responsiveness when challenged by subsequent heterologous triggers. This process is regulated at the cellular level (also known as peripheral trained immunity) and system-level (also known as centrally trained immunity). β-Glucan, MDP, and BCG are three of the most common inducers that contact the PRR of innate immune cells and release cytokines through signaling pathways, metabolic pathways, and epigenetic remodeling. β-Glucan recognizes the dectin-1 receptor and passes signal into cells via the AKT/mTOR/HIF1α pathway, promoting metabolic conversion from oxidative phosphorylation to aerobic glycolysis. Metabolites like fumarate can apply the inhibitory effect to the activity of KDM5, inducing the enrichment of H3K4me3 on promoters, and acetyl-CoA can also promote acetylation H3K27ac, resulting in an epigenetic rewriting. When stimulation is removed, some of the chromatin marks remain on histones and get ready for a faster modification and enhanced proinflammatory gene transcription upon re-stimulation, thus releasing more proinflammatory cytokines such as IL-6 IL-1β, TNFα, and IFNs. Rapamycin and metformin can nullify cytokine production via inhibiting mTOR, and ascorbate can abrogate trained innate immunity via inhibiting HIF1α. MDP and BCG can activate downstream NF-κB by interacting with intracellular NOD2 receptors, leading to epigenetic changes in H3K4me, H3K18ac, and H3K27ac. Butyrate can suppress the activation of trained innate immunity by preventing the acetylation of histone. Another important regulatory layer is HSPCs cells, which enable peripheral mature myeloid cells to be maintained for a longer period despite their short half-life. Inflammatory cytokines GM-CSF, IL-1β, and IFNs produced by innate immune cells can modulate myeloid progenitor cells in the bone marrow to promote myelopoiesis and generate trained monocytes. These two mechanisms play an important role in trained innate immunity