Hazy, Amanda Dawn2021-02-282021-02-282019-09-06vt_gsexam:21979http://hdl.handle.net/10919/102505Traumatic brain injury (TBI) is a major health concern in the United States and worldwide and effective treatment options are limited. Differences in the magnitude and characteristics of the peripheral-derived immune cell response to TBI are key contributors to the secondary cascades of damage following brain trauma, and means of modifying this response to improve clinical outcome are a current area of active research. Our work elucidated the peripheral immune response to TBI by characterizing the transcriptomic profile of juvenile vs adult peripheral immune cells following TBI as well as discovering a novel role for the tyrosine kinase receptor EphA4 in the peripheral-derived immune response to brain trauma. Previous work has demonstrated significant differences in recovery from TBI in young vs adult animals, and some studies have indicated that the immune response contributes to these differences. We utilized next-generation sequencing to compare gene expression profiles of blood cell fraction samples in juvenile and adult mice. Our work demonstrated that juvenile peripheral immune cells show a more dynamic response to TBI than adult and that pattern recognition receptor signaling is a cornerstone of these differences. To assess the specific mechanisms involved in the peripheral response to TBI, we utilized a bone marrow chimeric mouse model lacking EphA4 in the hematopoietic compartment. These studies found decreased lesion infiltration of peripheral immune cells, specifically activated macrophages, in the absence of EphA4. We also showed that EphA4 interacts with the Tie2/Angiopoietin signaling axis to regulate macrophage phenotype on the M1/2 continuum. Overall, our work demonstrated a novel role for EphA4, mediated by Tie2, as a pro-inflammatory regulator of the peripheral-derived immune cell response to TBI.ETDIn Copyrighttraumatic brain injuryperipheral-derived immune responseEphA4macrophagesThesis