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TGFbR signaling in squamous epithelial cells plays a fundamental role in controlling tissue specific allergic inflammation

ABSTRACT: Allergic diseases are becoming a global health crisis. Individuals harboring loss-of-function variants in transforming growth factor beta receptor (TGFbR) have an increased prevalence of allergic disease, but the mechanisms responsible are poorly understood. We demonstrate that mice harboring a variant identified in patients spontaneously develop disease that clinically, immunologically, histologically, and transcriptionally recapitulates eosinophilic esophagitis, a condition characterized by allergic inflammation in the esophagus. Diminished TGFbR signaling impairs epithelial cell maturation, resulting in local expression of inflammatory mediators that drive accumulation and activation of eosinophils, mast cells, T cells, and innate lymphoid cells. Our work reveals a fundamental, non-redundant, cell-intrinsic role for TGFbR signaling in epithelial cells needed to maintain immune homeostasis and prevent allergic inflammation, independent of barrier function or adaptive immune tolerance. Moreover, we demonstrate that epithelial dysfunction alone is sufficient to initiate and perpetuate allergic inflammation, which has implications for the prevention and treatment of allergic diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE193756 | GEO | 2023/01/15

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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TGFbR signaling in squamous epithelial cells plays a fundamental role in controlling tissue specific allergic inflammation

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