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Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor.

ABSTRACT: As a sensor of polyaromatic chemicals the aryl hydrocarbon receptor (AhR) exerts an important role in immune regulation besides its requirement for xenobiotic metabolism. Transcriptional activation of AhR target genes is counterregulated by the AhR repressor (AhRR) but the exact function of the AhRR in vivo is currently unknown. We here show that the AhRR is predominantly expressed in immune cells of the skin and intestine, different from other AhR target genes. Whereas AhRR antagonizes the anti-inflammatory function of the AhR in the context of systemic endotoxin shock, AhR and AhRR act in concert to dampen intestinal inflammation. Specifically, AhRR contributes to the maintenance of colonic intraepithelial lymphocytes and prevents excessive IL-1? production and Th17/Tc17 differentiation. In contrast, the AhRR enhances IFN-?-production by effector T cells in the inflamed gut. Our findings highlight the physiologic importance of cell-type specific balancing of AhR/AhRR expression in response to microbial, nutritional and other environmental stimuli.

SUBMITTER: Brandstatter O

PROVIDER: S-EPMC4869119 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor.

Brandstätter Olga O Schanz Oliver O Vorac Julia J König Jessica J Mori Tetsushi T Maruyama Toru T Korkowski Markus M Haarmann-Stemmann Thomas T von Smolinski Dorthe D Schultze Joachim L JL Abel Josef J Esser Charlotte C Takeyama Haruko H Weighardt Heike H Förster Irmgard I

Scientific reports 20160517

As a sensor of polyaromatic chemicals the aryl hydrocarbon receptor (AhR) exerts an important role in immune regulation besides its requirement for xenobiotic metabolism. Transcriptional activation of AhR target genes is counterregulated by the AhR repressor (AhRR) but the exact function of the AhRR in vivo is currently unknown. We here show that the AhRR is predominantly expressed in immune cells of the skin and intestine, different from other AhR target genes. Whereas AhRR antagonizes the anti ...[more]

PMID: 27184933

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Project description:Rationale: Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered as an important regulator for immune diseases. We have previously shown that AhR protects against allergic airway inflammation. The underlying mechanism, however, remains undetermined. Objectives: We sought to determine whether AhR specifically in Type II alveolar epithelial cells (AT2) modulates allergic airway inflammation and its underlying mechanisms. Methods: The role of AhR in AT2 cells in airway inflammation was investigated in a mouse model of asthma with AhR conditional knock out mice in AT2 cells (Sftpc-Cre;AhRflox/flox). The effect of AhR on allergen-induced autophagy was examined by both in vivo and in vitro analyses. The involvement of autophagy in airway inflammation was analyzed by using autophagy inhibitor chloroquine. The AhR-regulated gene profiling in AT2 cells was also investigated by RNA-seq analysis. Results: Sftpc-Cre; AhRflox/flox mice showed exacerbation of allergen-induced airway hyperresponsiveness and airway inflammation with elevated Th2 and airway epithelial-derived cytokines in bronchoalveolar lavage fluid (BALF). Notably, an increased allergen-induced autophagy was observed in the lung tissues of Sftpc-Cre; AhRflox/flox mice when compared with wild-type mice. Further analyses suggested a functional axis of AhR-TGF-β1 that is critical in driving allergic airway inflammation through regulating allergen-induced cellular autophagy. Furthermore, inhibition of autophagy suppressed allergic airway inflammation with decreased Th2 and epithelial cell-derived cytokines in BALFs. Additionally, RNA-seq analysis suggests that autophagy is one of the major pathways and CALCOCO2/NDP52 and S1009 are major autophagy-associated genes in AT2 cells that contribute to the AhR-mediated allergic airway inflammation. Conclusion: These results suggest that AhR in AT2 cells functions as a protective mechanism against allergic airway inflammation through controlling cell autophagy.

Dataset Information

Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor.

Publications

Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor.

Similar Datasets

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