Date Available

6-2-2023

Year of Publication

2022

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Neuroscience

First Advisor

Dr. Adam Bachstetter

Second Advisor

Dr. Linda Van Eldik

Abstract

Across the world, over 69 million people sustain a traumatic brain injury (TBI) per year making TBI a major health concern worldwide. Of all the TBIs that occur each year, it is suggested that up to 90 percent are mild in nature. Even a mild TBI causes both physical damages to the cells of the brain and activation of a variety of biochemical cascades. Inflammation is an extremely common pathology seen in the brains of TBI survivors of all severities. Chronic inflammation can cause detrimental effects within the brain including neurodegeneration. A major pro-inflammatory cytokine, interleukin-1 (IL-1), is upregulated within hours of the physical insult and can persist through activation of several different cell types within the brain. Interluekin-1 binds mainly to IL-1 receptor 1 (IL-1R1) which is expressed on endothelial cells 10-fold more than other cell types in the brain. While historically understudied in TBI, endothelial cells present a unique target for pre-clinical studies. Endothelial cells are not only disrupted by TBI in structure and function, but they can also respond to and release inflammatory signals to participate in the post-TBI inflammatory response. We thus focused on IL-1R1 and endothelial IL-1 signaling following a mild TBI animal model. We hypothesized that following mild TBI, brain endothelial cells serve as a mediator of neuroimmune responses via IL-1R1. Our mild closed head injury (CHI) model causes an increase in IL-1R1 expression in several brain regions after injury. Further, we found that our model induced inflammatory processes within 9 hours post-CHI which had mostly recovered by 72 hours. However, in an IL-1R1 global knock-out and endothelial-only restore model, we found a shifted inflammatory profile. We believe that this suggests the importance of communication between multiple cell types for IL-1 signaling in the brain following mild TBI. Thus, future studies into post-traumatic inflammation should focus on cell communication events to attempt to reduce inflammation and improve recovery.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.222

Funding Information

NIH, NINDS F31 "Understanding the immune response after mild TBI: Do endothelial cells play a major role?" 1 F31 NS116912-01 2020-2022

NIH T32 "Neurobiology of CNS Injury and Repair" 5T32NS077889-09 2022

NIH. RO1 "Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury" R01 NS103785 2018-2022

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