The Peripheral-Central Neuroimmune Interface: The Influence of Monocyte Reprogramming on Chronic Neuroinflammation in the Dentate Gyrus Following Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a leading cause of chronic morbidity with over 3 million people in the US alone living with a TBI-induced long-term disability. While the immediate effects of the impact itself can be devastating, long-term neurocognitive sequelae are most commonly due to ongoing secondary injury driven by chronic neuroinflammation. The dentate gyrus (DG) is a specialized region of the hippocampus responsible for memory contextualization and mood regulation. The DG also acts as a gateway organizing signals between the cortex and outer hippocampus, and hilar interneurons located in this region are critical for maintaining tight regulation of excitatory and inhibitory impulses. These interneurons are selectively vulnerable to secondary brain injury, leading to impaired cognitive and behavioral function. Peripheral-derived mononuclear cells (PDMs), namely monocytes and macrophages, have been recently implicated as key drivers in chronic neuroinflammation. Previous work has demonstrated that EphA4 is upregulated in infiltrating monocytes following brain injury and that blockade of EphA4 causes PDMs to adopt a less inflammatory, pro-resolving phenotype. Despite these findings, the precise, long-term impacts of infiltrating PDM activity on the DG microenvironment and interneuron populations has never been investigated. I hypothesize that a persistent PDM-driven proinflammatory cytokine profile drives hilar interneuron loss, and that deletion of EphA4 in monocytes would limit neuronal loss and improve long-term memory and mood outcomes through modulation of the local cytokine profile and reducing chronic glial activation. The work included in this dissertation characterized the temporospatial profile of the dentate gyrus microenvironment over four months following TBI and determined that chronic hilar interneuron loss and cognitive decline are associated with TNF-TNFR signaling. These studies also determined that EphA4 deletion in monocytes reduced hilar interneuron loss, chronic glial activation, and improved long-term neurobehavioral outcomes through downregulation of classical proinflammatory TNF and NF-κB signaling pathways. In addition, dual deletion of monocyte-specific EphA4 and Tie2 reversed these neuroprotective effects, indicating that PDM-associated EphA4/Tie2 signaling may be a key target for future therapeutic strategies.