Microglial Dual Nature in Maintaining Spatiotemporal Homeostasis
Microglia are highly dynamic tissue-resident macrophages that continuously adapt their functional states to developmental, environmental, and pathological cues within the central nervous system (CNS). Rather than executing fixed genetic programs, microglial phenotypes emerge from continuous integration of developmental origin, regional niche, metabolic status, neuronal activity, and environmental signals. In early brain development, microglia contribute to neural circuit refinement through phagocytosing apoptotic cells and extraneous synapses in an activity-dependent manner. In contrast, in the mature CNS, they continuously monitor their surroundings, maintaining synaptic homeostasis and rapidly responding to local tissue perturbances. However, perturbations in the spatiotemporal coordination of state transitions, such as ageing, metabolic dysregulation, and chronic disease, can redirect microglia toward maladaptive phenotypes characterized by long-term inflammation, impaired phagocytosis, and neuronal damage. Building upon recent advances in single-cell transcriptomics, spatial biology, and systems neuroscience, this review synthesizes current understanding of how developmental programming, regional specialization, temporal regulation, and metabolic adaptation collectively shape dynamic microglial states across health and disease. Finally, we discuss emerging therapeutic strategies aimed at context-dependent modulation of microglial states while highlighting current challenges and unanswered questions for precision microglial therapies. Graphical Abstract Microglia are highly plastic CNS-resident immune cells whose functional states are continuously shaped by developmental history, spatial niche-derived signals, temporal regulation, metabolic remodeling, and local microenvironmental cues. Rather than progressing through fixed activation programs, microglia dynamically transition among homeostatic, adaptive, and maladaptive states according to physiological demands and disease context. Failure to appropriately regulate these state transitions promotes chronic neuroinflammation, impaired phagocytosis, metabolic dysfunction, and neurodegeneration. Consequently, emerging therapeutic strategies increasingly focus on restoring physiologically coordinated microglial state dynamics through spatiotemporally informed modulation of signaling pathways, immunometabolism, epigenetic programs, and tissue-specific regulatory networks. (This figure was initially generated with the assistance of an AI tool (ChatGPT) and subsequently substantially modified by the authors to ensure scientific accuracy and originality.)