Assistant Professor Georgetown University Washington, District of Columbia
Abstract Text:
Background: Traumatic Brain Injury (TBI) is a major cause of disability and mortality, particularly among young adults and the elderly. Along with age, neuroinflammation plays a key role in contributing to negative outcomes after TBI. Meningeal lymphatics link the brain and periphery and play an important bi-directional inflammatory role, with particular involvement in the drainage of immune cells. It has been previously shown that disruption of this system exacerbates inflammation in Alzheimer’s disease, however how meningeal lymphatics influence immune responses after TBI is yet to be fully investigated. Here, we utilized high-throughput sequencing to investigate the transcriptional response of the meninges after TBI in young and aged mice.
Methods: Sham or TBI (controlled cortical impact) surgery was performed on 3 and 18-month C57Bl/6 wildtype mice. In both cohorts, functional assessment in the T-Maze was performed before brains were collected at 7d and 1-month post-injury (n=6 per timepoint), isolation of meninges followed by unbiased whole transcriptome RNAseq analysis.
Results: At 7d and 1m post injury, aged mice displayed worse outcomes in the T-Maze, suggesting the potential of increased inflammation influencing cognitive outcomes in aged mice after TBI. Following transcriptomic profiling of the meninges from all groups, principal component analysis (PCA) revealed age was the key factor in influencing the number of differentially expressed genes (DEGs), with clustering clearly delineated by the factor of young vs aged groups. At 7dpi, volcano analysis revealed 453 DEGs in Young TBI vs Young Sham groups and 256 DEGs in Aged TBI v Aged Shams. Despite this elevated number of altered genes in Young TBI groups, Aged mice had sustained expression over time (sustained expression of these genes through both timepoints- 7d and 1m). Interestingly, 792 differentially expressed genes were identified when comparing Young Sham mice with Aged Sham mice, and 983 DEGs when comparing Young TBI mice with Aged TBI mice. This indicates that aging profoundly affects meningeal gene expression and that head trauma in aging results in even larger changes in gene expression. Further investigation of the aged-based comparisons of the 792 altered genes using gene ontology, revealed that these enriched genes play key roles in immunoglobulin production (GO:0002377), immune response (GO:0006955), regulation of B cell activation (GO:0050864) and lymphocyte activation (GO:0046649). Closer inspection found highly significant upregulations in genes related to the immunoglobulin heavy chain (Ighm, Igha), light chain (Igkc), components of IgA or IgM antibodies (Jchain) and genes that regulate B cell infiltration (CD antigens).
Conclusion: Collectively these data demonstrate the time-course of meningeal specific signatures, providing insights into how age leads to worse neuroinflammatory outcomes in TBI. Further investigation in the meningeal inflammatory response may aid our capability to design better therapeutics for aged v young TBI patients.
