Microglial Innate Immune Memory: Implications and Research Advances in Central Nervous System Disorders

The central nervous system (CNS), comprising the brain and spinal cord, represents the core regulatory hub of the body. Damage to the CNS often leads to irreversible structural and functional impairments of neural tissues, posing a major global public health challenge. Immune memory encompasses two states: immune training and immune tolerance, which are characterized by enhanced or attenuated immune responses, respectively, following initial exposure to external stimuli in immune cells such as monocytes and macrophages. Microglia, the resident immune cells of the CNS, can be rapidly activated by external stimuli. Accumulating evidence indicates that microglial immune memory plays a critical role in sustaining states and neuroinflammatory responses in CNS disorders. Specifically, the immune training state promotes amyloid-β (Aβ) accumulation in the brains of Alzheimer's disease (AD) model mice, thereby exacerbating neuronal damage, whereas the immune tolerance state suppresses pro-inflammatory cytokine expression and alleviates neuroinflammation. This review focuses on two immune memory states in microglia-training and tolerance-and what triggers them. We summarize their roles and mechanisms in CNS diseases. Specifically, we break down how epigenetic and metabolic reprogramming control microglial immune memory, with an emphasis on how these two processes interact during memory formation and maintenance. Our goal is to fill key knowledge gaps about their combined effects and to suggest new therapeutic targets. Evidence shows that immune memory acts as a "double-edged sword" in the CNS: it can either fuel harmful inflammation and worsen damage, or, when moderately activated, protect nerves. Therefore, precisely balancing these two states could help reduce harmful inflammation while preserving the protective functions of microglia, offering a new, reversible immunotherapy for CNS diseases.