Schanz, Jan Oliver: The role of the AhR signaling pathway in regulation of gut-associated immune cells. - Bonn, 2018. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc:
author = {{Jan Oliver Schanz}},
title = {The role of the AhR signaling pathway in regulation of gut-associated immune cells},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2018,
month = jul,

note = {The aryl hydrocarbon receptor (AhR) is an important sensor for environmental polyaromatic chemicals and plays an essential role in immune regulatory processes, including maintenance of intestinal barrier integrity. AhR activity is regulated through the AhR repressor (AhRR), which is encoded by an AhR target gene. Regulation and interplay of AhR and AhRR, however, remain largely elusive. Using AhRR/EGFP-reporter mice it could be shown that the AhRR is specifically expressed in immune cells of barrier organs, but not in intestinal epithelial cells, different from the more widespread expression of the AhR. Similar to AhR-knockout mice, AhRR-deficient mice are highly susceptible to dextran sodium sulfate (DSS)-induced colitis.
In this PhD thesis it could be shown that enhanced colitis susceptibility in AhRR-deficient mice was accompanied by enhanced Th17/Tc17 and reduced Th1/Tc1 frequencies in the gut. In contrast, AhR-deficiency resulted in accumulation of both Th17/Tc17 and Th1/Tc1 cells in the intestine. A decreased frequency of intestinal ILC3s, previously held responsible for colitis susceptibility in AhR-/- mice, was not observed in AhRR-deficient mice. Yet, significantly elevated IL-1β levels could be detected in steady-state colon tissue of AhRR-deficient mice, indicating enhanced activation of the innate immune system. Using conditional macrophage- and neutrophil-specific AhRR-knockout mice, it could be shown that these cells types do not convey the enhanced DSS colitis susceptibility noticed in complete AhRR-deficient mice.
Moreover, it was shown that cell type-specific AhRR expression in intestinal immune cells is driven by dietary AhR ligands, whereas depletion of microbiota by treatment with broad-spectrum antibiotics had no effect on AhRR expression. Further, it could be confirmed that lack of dietary AhR ligands deteriorates the mucosal intestinal barrier, whereas AhR ligand supplementation improves barrier integrity and protects from DSS-induced colitis. Interestingly, other synthetic diets like High fat diet and matched control diet protect against DSS-induced colitis, despite low AhR ligand content, highlighting the existence of other diet related pathways besides AhR signaling with great importance for the intestinal barrier function.
Overall the findings of this thesis underline the physiologic importance of cell-type-specific balancing of AhR/AhRR signaling in response to microbial, nutritional and inflammatory stimuli.},

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