Date of Award

Summer 2019

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Mitzi Nagarkatti

Abstract

Aryl hydrocarbon receptor (AhR), is a ligand-activated transcription factor that integrates environmental, dietary, microbial and metabolic cues to control various cellular processes, such as the cell cycle, epithelial barrier function, cell migration and immune function. AhR was discovered as the receptor that binds with high affinity to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and leads to numerous of toxicological outcomes. In the current study, we discovered a critical role played by AhR, following activation by TCDD, in modulating a variety of immunological functions through regulation of epigenetic and microbial pathways. Our data demonstrated that AhR activation triggers MDSC mobilization from bone marrow to peritoneal cavity which correlated with increased levels various of chemokines and their receptors and induced epigenetic changes via modulation of small noncoding RNA molecules and targeted genes. These MDSCs had high levels of immunosuppressive activity and energy metabolic rate. Also, our data provided a novel link between gut microbiome alterations and MDSC induction and function in colon after TCDD administration. Additionally, we provide evidence that Resveratrol, a natural polyphenol compound is capable to attenuating the immunotoxicological effect of TCDD by altering the migration, differentiation, and suppressive function of MDSCs. Together, our studies demonstrate that AhR can be targeted to suppress inflammation and thus treat inflammatory and autoimmune diseases as well as cancer.

Available for download on Wednesday, August 18, 2021

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