Date of Award

Summer 2019

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Mitzi Nagarkatti

Abstract

Inflammation is considered to be the underlying cause of a majority of clinical disorders. Thus, studies aimed at understanding the signaling pathways that trigger inflammation could have significant translational impact. In the current study, we investigated the effect of activation of cannabinoid (CB) and Aryl hydrocarbon hydroxylase (AhR) receptors on the inflammatory response. To that end, we used cannabinoids such as Δ (9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD), and a well-established AhR agonist namely 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). These were tested against two inflammatory disease models: 1) Experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis (MS), and 2) Exposure to pertussis toxin (PTX), an exotoxin produced by the bacterium, Bordetella pertussis, which causes whooping cough. We observed that combination of THC and CBD resulted in attenuation of EAE clinical scores and reduced proinflammatory cytokines secretion like IL-17A, IFN-γ, IL-6, TNF-α and IL-1β in the mononuclear cells of the brain. Treatment of EAE mice with cannabinoids also led to decrease in immune cell infiltration in the CNS, marked amelioration of CNS tissue destruction, and reduced demyelination when compared to control mice. Additionally, treatment with these cannabinoids led to cell cycle arrest and cell death in activated T cells. MicroRNA (miRNA) microarray analysis, revealed altered miRNA profile in brain infiltrating mononuclear cells following treatment with combination of THC and CBD that promoted anti-inflammatory pathways. Interestingly, THC+CBD treatment of EAE mice caused alterations in gut microbiota with a decrease in the population of Akkermansia muicinphila, the bacteria that are increased in MS patients and involved in the pathogenicity of MS. In addition, THC+CBD treatment increased the production of a wide range of short-chain fatty acids (SCFAs) that are anti-inflammatory. In mice treated with PTX, there was significant induction of inflammation with an increase TH17 and TH1 proliferation. AhR activation in PTX-treated mice with TCDD, led to increased induction of FoxP3+ Treg cells and myeloid-derived suppressor cells (MDSC) that are highly immunosuppressive. In addition, TCDD altered the expression of microRNAs that promoted anti-inflammatory T cell phenotype. Together, the current study demonstrates that activation of CB and AhR on immune cells leads to epigenetic modulations as well as alterations in microbiota that promote anti-inflammatory signaling pathways. The current study suggests that targeting CB and AhR constitutes a unique therapeutic modality to treat inflammatory diseases.

Rights

© 2019, Zinah Zamil Al-Ghezi

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