Revisiting the critical roles of reactive microglia in traumatic brain injury

Traumatic brain injury (TBI) triggers a complex neuroinflammatory cascade, with microglia serving as key regulators of both pathological damage and tissue structural restoration. Despite extensive research, the precise temporal evolution of microglial activation and its implications for long-term neurological outcomes remain incompletely understood. Here, we provide a comprehensive review of the molecular and cellular mechanisms underlying microglial responses in TBI, highlighting their role in neuroinflammation, neurogenesis, and tissue remodeling. We systematically compare clinical and preclinical TBI classifications, lesion patterns, and animal modeling strategies, evaluating their translational relevance. Furthermore, we explore the limitations of the conventional M1/M2 dichotomy and emphasize recent insights from single-cell transcriptomic analyses that reveal distinct microglial subpopulations across different injury phases. Finally, we discuss current therapeutic strategies targeting microglial modulation and propose future directions for neuroimmune interventions in TBI. By integrating findings from experimental and clinical studies, this review aims to bridge mechanistic insights with therapeutic advancements, paving the way for precision-targeted neuroimmune therapies.