The Meningeal Response to Traumatic Brain Injury

Traumatic brain injury (TBI) is a devastating event that results in a heightened risk for long- term disease sequelae including anxiety, depression, Alzheimer’s disease (AD) and chronic traumatic encephalopathy. TBI affects 12% of the adult population; yet, our mechanistic understanding of the factors that render the TBI brain more susceptible to neurological disease remains poorly understood. Recent findings point to dysregulated and sustained immune responses as contributing to negative outcomes. However, why inflammatory responses persist in the brain long after injury is still largely unknown.

In this dissertation, we examine the meningeal tissue and its response to brain injury. The meninges serve as the interface between the brain and the immune system, and facilitate many important brain-immune interactions both in health and disease. We couple a bioinformatic approach to determine gene expression alterations in meningeal tissue following TBI with experimental methods for interrogating how the meningeal lymphatic system specifically influences TBI pathogenesis.

To determine how the meningeal lymphatic system affects TBI pathogenesis, we utilized an experimental mouse model of TBI to demonstrate that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last at least one month post- injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

To further elucidate the meningeal response to TBI, we utilized single cell and bulk RNA sequencing one week post injury to determine how different cell populations within the meninges are affected by injury. We found that the meninges are a heterogeneous tissue that includes many types of immune cells, fibroblasts and endothelial cells. We find that following a mild TBI, there are increases in frequencies of meningeal macrophages and fibroblasts. These cells undergo upregulation of inflammatory related genes. Moreover, we find that the meningeal response to TBI is substantially altered in aging, even 1.5 months post injury.

In this dissertation, we examined the meningeal responses to TBI. The findings here present novel insights into the role of the meningeal lymphatic system and the meninges as a whole in shaping the immune response following brain injury. These findings will allow for a deeper understanding of the immune responses following brain injury with the goal of eventually developing therapies to mitigate negative long-term outcomes following brain injury.