Regulation of Intestinal Epithelial Thymic Stromal Lymphopoietin Gene Expression by Retinoic Acid Receptor Alpha
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2021-08-23
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Abstract
Inflammatory bowel disease is characterized by chronic inflammation of the gastrointestinal tract. The pathogenesis is thought to be due to a dysregulated immune response to intestinal microbiota. Approximately 15% of the risk is genetically linked and approximately 85% is attributed to environmental exposures. Dietary factors like retinoic acid (RA), a vitamin A metabolite, have been linked to the onset of IBD by influencing intestinal immune function. RA induces Tregs and inhibits the actions of proinflammatory Th-17 cells. We have previously described decreased CD103+ DCs numbers in the intestinal compartments of RARα-deficient mice (RARαvillin mice). We sought to generate an experimental system to identify signaling pathway(s) or mechanism(s) that might be governing these effects, specifically RA signaling, as this data suggested there might be contributing factors intrinsic to IECs. We chose to establish a knockout cell line using the CRISPR/Cas9 system, given its affordability and efficiency compared to other in vitro models, and used it to study the effects of RAR⍺ ablation in IECs. Thus, our hypothesis was that RA signaling regulates the expression of lymphokines and other immune mediators (e.g., TSLP) by IECs, which then modulate the intestinal immune compartment. We hypothesized TSLP could be contributing to the decrease in CD103+ DCs as it is an important cytokine involved in TH2-type immunity and plays a key role in the maintenance of peripheral CD4+ T cell homeostasis by modulating the activation/maturation of myeloid cells. We used the CRISPR/Cas9 system to examine the effects of RARα ablation and its role in regulating intestinal epithelial TSLP expression. We found that TSLP expression is controlled by RARα in IECs where it may act as a repressor of TSLP promoter transactivation. This suggests an important role for RA signaling on myeloid/T cell function via effects on TSLP gene expression.
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Mahmood, R. (2021). Regulation of Intestinal Epithelial Thymic Stromal Lymphopoietin Gene Expression by Retinoic Acid Receptor Alpha (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.