Date of Award
Open Access Dissertation
Host immunity is a complicated system of pro-inflammatory and anti-inflammatory processes that respond to exogenous and endogenous threats to regulate host physiology, inhibit carcinogenesis, and protect from infections. Sustained deviance from normal immunological function occurs due to a variety of factors both endogenous and exogenous, with some factors that can dysregulate host immunity including: genetics, microbiota composition, toxin exposure, age, gender, and smoking. The etiology of inflammatory disorders is both convoluted and complex due to the sheer number of facets regulating host immunity. To better contribute to understanding how immunological dysregulation occurs we focused on how three anti-inflammatory compounds (tryptamine, CBD, and TCDD) suppress inflammation, primarily with a focus on autoimmune neuroinflammation in a murine model of MS. MS is an incurable neurodegenerative perpetuated by the host immune system inadvertently recognizing--and inflammatory cascades directed at--peptides present in the myelin sheathing within the CNS. The encephalitogenic immunity of MS is characterized by overabundances of pro-inflammatory immune cells, such as Th17 and macrophages, driving neurodegenerative inflammation in a normally immunologically privileged site. Simultaneous to this increase in inflammatory processes in the CNS is an anti-parallel reduction of the regulatory processes, carried out by Tregs and MDSCs, that fight to maintain an immunologically privileged CNS. Sustained neuroinflammation in MS results in paralytic symptoms and atrophy that no current medications can fully reverse, therefore putting an emphasis on the need for potential therapeutics. Our main findings demonstrate that tryptamine and CBD are both capable of significantly ameliorating paralytic symptoms in murine model of MS known as EAE, and that acute TCDD exposure leads to metabolomic disbalance that can contribute to immunotoxicity following exposure. Namely, we demonstrated that tryptamine ameliorates EAE via inhibiting encephalitogenic CD4+ T cells in an AHR dependent manner, and that CBD ameliorates EAE by inhibiting IL-1β expression and subsequently the myeloid-mediated immune response. Our studies regarding TCDD exposure demonstrate that changes in the circulating and cecal metabolome likely contribute to the suppression of NFκB and ERK1/2 activity following exposure. Collectively, these studies contribute to the etiological understanding of the mechanisms that drive immunological dysfunction and suggest therapeutics for treating autoimmune neuroinflammation and the correcting of metabolomic disbalance following dioxin exposure.
Dopkins, N.(2021). Regulation of Inflammatory Processes by Tryptamine, Cannabidiol and 2,3,7,8-Tetrachlorodibenzo-P-Dioxin. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/6416
Available for download on Tuesday, August 15, 2023