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

Brittany P Todd, Zili Luo, Molly J E Larson, Polly J Ferguson, Alexander G Bassuk and Elizabeth A Newell
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Research Square
06/06/2026
DOI: 10.21203/rs.3.rs-9785030/v1
PMCID: PMC13252574
PMID: 42281997
url
https://doi.org/10.21203/rs.3.rs-9785030/v1View
Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

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.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.
 microglia type I interferon traumatic brain injury

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