Despite its prevalence, there are currently zero treatments available for traumatic brain injuries (TBI). Neuroinflammation is a key aspect of the secondary injury process, but remains poorly understood. Recent work has shown that Type I Interferons, inflammatory cytokines typically produced in response to viral infection, are present in the post-mortem brains of human TBI patients. The cyclic GMP-AMP Synthase- Stimulator of Interferon Genes (cGAS-STING) pathway is one of the primary methods of producing Type I IFNs; therefore, this work sought to evaluate the role of the cGAS-STING pathway in a murine controlled cortical impact (CCI) model of TBI. Using cGAS knockout (KO) or STING KO mice, we show that global loss of either protein results in substantial neuroprotection. One day after injury, animals have reduced lesion size, cell death, and inflammatory cytokine production, as well as reduced motor deficits several days after injury. We also determined that mitochondrial DNA (mtDNA) is present in the cytosol of injured cortical cells, indicating it is available to bind cGAS, a cytosolic pattern recognition receptor. To determine whether brain-resident or peripheral immune cells are responsible for detrimental cGAS-STING signaling after TBI, we utilized bone marrow chimeric animals lacking STING in either the brain or hematopoietic cells and animals lacking STING specifically in microglia. We found that both microglia and peripheral immune cells contribute to STING signaling after neurotrauma, and that loss of STING in either cell population is beneficial. Taken together, this work demonstrates that canonical, cGAS-dependent STING signaling occurs primarily in microglia and peripheral immune cells, resulting in detrimental neuroinflammatory events after TBI. / Doctor of Philosophy / Traumatic brain injuries (TBI), including concussions and more severe injuries, are a leading cause of death and disability across the globe; yet, there are no Food and Drug Administration (FDA) approved treatments. There are two phases in the injury: primary injury, which is the immediate damage to brain cells upon impact, and secondary injury, which includes a wide range of cellular processes in the minutes to weeks after injury. Because the primary injury is so rapid, we utilize safety measures, such as helmets, to limit the severity of the TBI. The secondary injury, however, occurs over a longer period of time; therefore, this is where most research is focused for developing potential treatments. Inflammation in the brain, termed neuroinflammation, is a key part of this secondary injury. While some inflammation is useful for clearance of damaged cells, too much inflammation can cause additional damage. The goal of this work was to examine how a specific inflammatory pathway, the cGAS-STING (cyclic GMP-AMP synthase- stimulator of interferon genes) pathway, contributes to neuroinflammation after brain injury.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/111993 |
| Date | 23 September 2022 |
| Creators | Fritsch, Lauren Elizabeth |
| Contributors | Graduate School, Pickrell, Alicia M., Theus, Michelle H., Allen, Irving C., VandeVord, Pamela J. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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