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

Abstract

Background 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. Although histologic glial reactivity is well established, a precise understanding of microglia and astrocyte function following trauma remains unknown. Methods Adult 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. Results Our 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. Conclusion Concurrent 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.

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model

“…We have found greater transcriptional activation of microglia specific markers, compared to astrocytes, which has been shown in vivo rodent injury studies as well (31). Some of the markers were not detected in our model (some examples are IFI209, OASL2, IFI27I2A, IRF9, and H2-Q4), due to species differences, and limitations of our model (lack of macrophages, blood vessels, and other factors) (31). Among upregulated genes in astrocytes were GBP3, IFIT3; and downregulated MAFB.…”

Deletion of the Autism-Associated Protein SHANK3 Abolishes Structural Synaptic Plasticity after Brain Trauma

“…Following mTBI, the microglia only proliferated in WT mice CA1 hippocampus on both the ipsilateral and contralateral sides. Even though microglia were increased only in WT mice after mTBI, we observed an increment in the activated (motile) and a reduction in the less activated (resting) microglia in both strains [ 47 ] on the ipsilateral side ( Figure 4 ). The observation that astrocytes and microglia increased also on the contralateral side indicates that the augmented gliosis occurring in the ipsilateral side is also seen in distant regions and may explain the loss of synaptic contacts [ 33 , 34 ].…”

Traumatic Brain Injury Induces cGAS Activation and Type I Interferon Signaling in Aged Mice

“…A recent study using a CCI model in young adult mice indicates that neurons release IFN-b in response to TBI which leads to activation of colocalized microglia (101). In contrast, Karve and colleagues provided evidence that peripheral immune cells drive the IFN-I response in the brain following TBI (12), while another recent RNAseq study identified unique microglial and astrocyte transcriptomes enriched for IFN-I following lateral fluid percussion injury in mice (102). Almost all cell types in the body can produce IFN-I (103), and it is likely that all damaged cells release IFN-I in the brain following TBI.…”