Microglia and neuroinflammation: An in-depth analysis from functional diversity to disease mechanisms.
BACKGROUND Microglia are essential regulators of central nervous system homeostasis and participate in immune surveillance, inflammatory regulation, phagocytosis, metabolic adaptation, and tissue repair. Recent single cell and spatial omics studies have revealed extensive microglial heterogeneity, challenging the traditional M1/M2 classification. However, the functional significance and therapeutic potential of distinct microglial states remain highly context dependent. METHODS This review summarizes recent advances in microglial biology across acute brain injury, neurodegenerative and demyelinating disorders, central nervous system infections, and psychiatric and neurodevelopmental diseases. Evidence from multiomics studies, genetic approaches, functional experiments, and emerging therapeutic strategies was integrated to evaluate mechanisms and translational challenges. RESULTS Microglial responses represent dynamic functional programs rather than fixed beneficial or detrimental phenotypes. Their effects on inflammation, phagocytosis, immune regulation, and tissue repair are determined by disease stage, anatomical location, and local microenvironment. Although microglia targeted therapies, including signaling modulation, depletion and repopulation, replacement strategies, and targeted delivery systems, show promise, clinical translation remains limited by insufficient human validation, model differences, and incomplete understanding of spatiotemporal regulation. CONCLUSIONS Microglial function should be interpreted within a context dependent framework integrating cellular state, functional outcome, disease stage, and therapeutic timing. Future studies should focus on cell specific validation and human translational approaches to develop precise microglia directed therapies. HIGHLIGHT Microglial responses are dynamic functional programs shaped by disease context, anatomical location, and temporal progression rather than fixed phenotypes. Single cell and spatial omics reveal extensive microglial heterogeneity, but functional validation remains essential to distinguish molecular states from biological outcomes. Context guided microglial modulation, including targeted delivery, immune regulation, depletion, and replacement strategies, provides new opportunities for precision therapy.