Trained immunity in neuroinflammation: emerging evidence, clinical perspectives, and future directions

Trained immunity is the ability of the innate immune system to mount a heightened response to an environmental stimulus after a previous encounter with a noxious trigger. This effect is mediated by metabolic rewiring and epigenetic reprogramming in innate immune cells. In the context of neuroinflammation, trained immunity may represent a major contributor to the pathogenesis of neurological diseases, exerting both detrimental and potentially beneficial effects. While the general mechanisms and systemic implications of trained immunity are widely discussed, evidence in central nervous system (CNS) diseases remains fragmented and largely confined to individual pathological conditions. As a result, a comprehensive framework integrating these findings and identifying shared mechanisms across neurological disorders is still lacking. In this review, we explore the concept of trained immunity with a focus on neuroinflammatory and neurodegenerative diseases, synthetizing evidence from multiple CNS pathologies, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and cerebrovascular disorders. We first critically examine preclinical and experimental studies addressing innate immune memory in the CNS and subsequently integrate these findings with emerging clinical evidence, aiming to identify convergent mechanisms and disease-relevant immune memory signatures. Finally, we discuss potential therapeutic targets identified in preclinical settings and outline key unresolved issues, including the nature of triggering stimuli, thresholds, and temporal dynamics shaping innate immune memory in the CNS. By highlighting current limitations and defining critical questions for future research, this review presents a unifying perspective on trained immunity in neurological diseases and underscores the translational potential to modulate neuroinflammation and to influence disease progression.