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Distinct roles of FOXA2 and FOXA3 in allergic airway disease

ABSTRACT: Allergen challenge induced mucus metaplasia modify the expression of two transcription factors belonging to the FOXA family: FOXA2 and FOXA3. Foxa2 expression is decreased during allergic airway disease whereas, Foxa3 expression is increased by allergen. Therefore, we asked whether persistent expression of Foxa2 prevents mucus and whether absence of Foxa3 affects mucus or other features asociated with allergic airway disease. We analyzed the effects of these changes in FOXA transcription factor expression using Foxa2 transgenic mice and Foxa3-/- mice. We found that persistent expression of FOXA2 reduced mucus but the absence of FOXA3 had no effect on mucus production induced by allergen challenge. However, the absence of FOXA3 decreased airway hyperreactivity and increased IgE production and eosinophilic inflammation but none of these features were affected by persistent expression of FOXA2. These results indicate that FOXA3 has functions distinct from those of FOXA2 in the allergic response. Keywords: gene expression comparison between Foxa3-/- and littermate control mice both challenged with OVA

ORGANISM(S): Mus musculus

PROVIDER: GSE13382 | GEO | 2009/08/21

SECONDARY ACCESSION(S): PRJNA109809

REPOSITORIES: GEO

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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.

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Distinct roles of FOXA2 and FOXA3 in allergic airway disease

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