Traumatic brain injury results in unique microglial and astrocyte transcriptomes enriched for type I interferon response

Brittany P Todd,Zili Luo,Alexander G Bassuk,Michael S Chimenti,Polly J Ferguson,Elizabeth A Newell

doi:10.1186/s12974-021-02197-w

Abstract

BackgroundTraumatic brain injury (TBI) is a leading cause of death and disability that lacks neuroprotective therapies. Following a TBI, secondary injury response pathways are activated and contribute to ongoing neurodegeneration. Microglia and astrocytes are critical neuroimmune modulators with early and persistent reactivity following a TBI. Although histologic glial reactivity is well established, a precise understanding of microglia and astrocyte function following trauma remains unknown.MethodsAdult male C57BL/6J mice underwent either fluid percussion or sham injury. RNA sequencing of concurrently isolated microglia and astrocytes was conducted 7 days post-injury to evaluate cell-type-specific transcriptional responses to TBI. Dual in situ hybridization and immunofluorescence were used to validate the TBI-induced gene expression changes in microglia and astrocytes and to identify spatial orientation of cells expressing these genes. Comparative analysis was performed between our glial transcriptomes and those from prior reports in mild TBI and other neurologic diseases to determine if severe TBI induces unique states of microglial and astrocyte activation.ResultsOur findings revealed sustained, lineage-specific transcriptional changes in both microglia and astrocytes, with microglia showing a greater transcriptional response than astrocytes at this subacute time point. Microglia and astrocytes showed overlapping enrichment for genes related to type I interferon signaling and MHC class I antigen presentation. The microglia and astrocyte transcriptional response to severe TBI was distinct from prior reports in mild TBI and other neurodegenerative and neuroinflammatory diseases.ConclusionConcurrent lineage-specific analysis revealed novel TBI-specific transcriptional changes; these findings highlight the importance of cell-type-specific analysis of glial reactivity following TBI and may assist with the identification of novel, targeted therapies.

Highlights

Traumatic brain injury (TBI) is a leading cause of death and disability that lacks neuroprotective therapies
Microglia were identified based on CD11b+ and CD45 intermediate expression, whereas astrocytes were identified based on ASCA2 expression (Fig. 1B)
We found a significant overlap between the two TBI models and the signature disease-associated microglia (DAM) genes

Summary

Introduction

Traumatic brain injury (TBI) is a leading cause of death and disability that lacks neuroprotective therapies. Following a TBI, secondary injury response pathways are activated and contribute to ongoing neurodegeneration. Microglia and astrocytes are critical neuroimmune modulators with early and persistent reactivity following a TBI. TBI is a leading cause of disability as individuals that survive often suffer persistent neurologic dysfunction. Secondary injury response pathways, including neuroinflammation, are triggered at the time of injury and contribute to ongoing neurodegeneration and neurologic dysfunction. Longitudinal experimental and clinical studies following TBI have both clearly demonstrated progressive neurodegeneration and brain atrophy, highlighting the impact of secondary injury processes [4, 5]. To identify novel therapies that will prevent TBI progression and improve outcomes for patients, neuroinflammation and other secondary injury pathways require ongoing study

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