Type I interferon signaling in microglia drives synaptic engulfment and neuronal loss following traumatic brain injury

Type I interferon (IFN-I) signaling has emerged as a central regulator of neuroinflammation across diverse central nervous system disorders, including traumatic brain injury (TBI). While TBI is a leading cause of neurologic morbidity and mortality through young adulthood, there is a paucity of neuroprotective therapies available to clinicians. Recent work has demonstrated neuroprotection after global IFN-I deficiency, yet the cell-type-specific contributions to traumatic brain injury (TBI) and the mechanisms of immune modulation remain poorly defined. Using mice with microglia-specific IFN-I receptor deficiency, we show that loss of microglial IFN-I responsiveness suppresses microglial reactivity, reducing microglial accumulation, synaptic engulfment, antigen presentation, and T cell interactions after TBI. This attenuation preserves neuronal integrity and limits thalamic neuronal loss. Despite this neuroprotection, microglia-restricted IFN-I blockade reveals functional redundancy across CNS cell types, underscoring the multi-cellular nature of IFN-I signaling in the injured brain. Together, our findings delineate a microglial IFN-I–dependent pathway that exacerbates secondary injury after TBI and highlight both the therapeutic potential and inherent limitations of cell-type-targeted IFN-I modulation.