The role of trained immunity in chronic non-communicable inflammatory diseases.

BackgroundTrained immunity, a form of long-term functional reprogramming of innate immune cells through epigenetic and metabolic changes, traditionally confers protection against infections. However, inappropriate activation by endogenous sterile stimuli can drive persistent maladaptive inflammation in non-communicable diseases (NCDs).ObjectiveThis systematic review synthesizes primary evidence for trained immunity in atherosclerosis, type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and neurodegenerative disorders, focusing on endogenous inducers, cellular mediators, mechanisms, and translational implications.Data Sources and MethodsFollowing PRISMA guidelines, we included original studies demonstrating trained immunity induced by sterile endogenous signals in the targeted diseases. Narrative synthesis was performed due to heterogeneity precluding meta-analysis.ResultsTwelve primary studies met the inclusion criteria. In atherosclerosis (n = 8 studies), oxLDL, aldosterone, Western diet lipids, and post-myocardial infarction signals induced trained immunity in monocytes or macrophages and hematopoietic progenitors via H3K4me3 enrichment, mTOR/NLRP3 activation, and glycolytic/fatty acid shifts, leading to persistent cytokine hyperproduction (TNF-α, IL-6), foam cell formation, and transmissible plaque progression. In T2DM/hyperglycemia (n = 3), high glucose levels triggered MLL-mediated epigenetic reprogramming and glycolysis-dependent "metabolic memory," which skewed myelopoiesis and accelerated atherosclerosis despite normoglycemia. In CKD (n = 1), indoxyl sulfate induced AhR-dependent arachidonic acid pathway activation with metabolic rewiring, sustaining systemic inflammation. In neurodegeneration (n = 1), peripheral stimuli caused epigenetic reprogramming in microglia, yielding hyperresponsive or tolerized states modulating amyloid-β pathology. Convergent mechanisms (H3K4me3, glycolysis, mTOR/AhR/NLRP3) highlight trained immunity as a shared driver of chronic sterile inflammation.ConclusionsTrained immunity emerges as a unifying maladaptive mechanism perpetuating low-grade inflammation across these diseases, bridging transient endogenous insults to sustained pathology. Targeting reprogramming pathways, such as glycolysis or epigenetic inhibitors, offers promising therapeutic strategies. Expanded human studies are needed to address preclinical dominance and data gaps, particularly in CKD and neurodegeneration, where evidence is preliminary.