Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, United States; Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States; Medical Scientist Training Program, University of Virginia School of Medicine, Charlottesville, United States; Immunology Training Program, University of Virginia School of Medicine, Charlottesville, United States
Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, United States
Arun B Dutta
Medical Scientist Training Program, University of Virginia School of Medicine, Charlottesville, United States; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, United States
Wei Feng Ma
Medical Scientist Training Program, University of Virginia School of Medicine, Charlottesville, United States; Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, United States
Katherine R Bruch
Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, United States
Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, United States; Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States; Medical Scientist Training Program, University of Virginia School of Medicine, Charlottesville, United States; Immunology Training Program, University of Virginia School of Medicine, Charlottesville, United States
Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, United States; Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States
Hannah E Ennerfelt
Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, United States
Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, United States; Medical Scientist Training Program, University of Virginia School of Medicine, Charlottesville, United States; Immunology Training Program, University of Virginia School of Medicine, Charlottesville, United States
Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders, however, we still lack fundamental knowledge about meningeal biology. Here, we utilized high-throughput RNA sequencing (RNA-seq) techniques to investigate the transcriptional response of the meninges to traumatic brain injury (TBI) and aging in the sub-acute and chronic time frames. Using single-cell RNA sequencing (scRNA-seq), we first explored how mild TBI affects the cellular and transcriptional landscape in the meninges in young mice at one-week post-injury. Then, using bulk RNA-seq, we assessed the differential long-term outcomes between young and aged mice following TBI. In our scRNA-seq studies, we highlight injury-related changes in differential gene expression seen in major meningeal cell populations including macrophages, fibroblasts, and adaptive immune cells. We found that TBI leads to an upregulation of type I interferon (IFN) signature genes in macrophages and a controlled upregulation of inflammatory-related genes in the fibroblast and adaptive immune cell populations. For reasons that remain poorly understood, even mild injuries in the elderly can lead to cognitive decline and devastating neuropathology. To better understand the differential outcomes between the young and the elderly following brain injury, we performed bulk RNA-seq on young and aged meninges 1.5 months after TBI. Notably, we found that aging alone induced upregulation of meningeal genes involved in antibody production by B cells and type I IFN signaling. Following injury, the meningeal transcriptome had largely returned to its pre-injury signature in young mice. In stark contrast, aged TBI mice still exhibited upregulation of immune-related genes and downregulation of genes involved in extracellular matrix remodeling. Overall, these findings illustrate the dynamic transcriptional response of the meninges to mild head trauma in youth and aging.
