Abstract: Microglia, the resident innate immune cells of the central nervous system (CNS), play important roles in brain development, maintenance, and disease. As brain sentinels, microglia adopt a surveillant state in healthy tissue characterized by a ramified scanning morphology that maintains CNS homeostasis and contributes to learning-associated synaptic plasticity. Following acute CNS injury or during chronic disease, microglia undergo dramatic morphological transformations and a phenotypic switch to an activated state that initially plays an important protective role against pathological insult (e.g., clearance of cellular debris by phagocytosis to facilitate effective wound healing responses). However, when microglial activation becomes chronic and dysregulated it can have detrimental effects and lead to neurodegenerative processes. Chronic microglial activation has been reported in patients who suffer moderate-to-severe traumatic brain injury (TBI) and is evident in white matter and distant sites from the primary lesion for many years after the initial brain trauma (Johnson et al., 2013). Microglia are also chronically activated up to 1 year following experimental TBI in rodents, and contribute to chronic neurodegeneration and cognitive impairments (Loane et al., 2014). Thus, chronic non-resolving inflammation with widespread microglial activation is a defining feature of moderate-to-severe TBI, and an important secondary injury mechanism that may be treatable (Simon et al., 2017).