AUTHOR=Wang Ji , Zhao Yilin , Zhang Xin , Tu Wei , Wan Rongjun , Shen Yingchun , Zhang Yan , Trivedi Ruchik , Gao Peisong 

TITLE=Type II alveolar epithelial cell aryl hydrocarbon receptor protects against allergic airway inflammation through controlling cell autophagy

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.964575

DOI=10.3389/fimmu.2022.964575

ISSN=1664-3224

ABSTRACT=<sec><title>Rationale</title><p>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.</p></sec><sec><title>Objectives</title><p>We sought to determine whether AhR specifically in type II alveolar epithelial cells (AT2) modulates allergic airway inflammation and its underlying mechanisms.</p></sec><sec><title>Methods</title><p>The role of AhR in AT2 cells in airway inflammation was investigated in a mouse model of asthma with AhR conditional knockout mice in AT2 cells (<italic>Sftpc-Cre;AhR<sup>f/f</sup></italic>). The effect of AhR on allergen-induced autophagy was examined by both <italic>in vivo</italic> and <italic>in vitro</italic> 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 sequencing (RNA-seq) analysis.</p></sec><sec><title>Results</title><p><italic>Sftpc-Cre;AhR<sup>f/f</sup></italic> mice showed exacerbation of allergen-induced airway hyperresponsiveness and airway inflammation with elevated Th2 cytokines in bronchoalveolar lavage fluid (BALF). Notably, an increased allergen-induced autophagy was observed in the lung tissues of <italic>Sftpc-Cre;AhR<sup>f/f</sup></italic> 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 with autophagy inhibitor chloroquine significantly suppressed cockroach allergen–induced airway inflammation, Th2 cytokines in BALFs, and expression of autophagy-related genes LC3 and Atg5 in the lung tissues. In addition, RNA-seq analysis suggests that autophagy is one of the major pathways and that <italic>CALCOCO2/NDP52</italic> and <italic>S1009</italic> are major autophagy-associated genes in AT2 cells that may contribute to the AhR-mediated cockroach allergen–induced airway inflammation and, subsequently, allergic asthma.</p></sec><sec><title>Conclusion</title><p>These results suggest that AhR in AT2 cells functions as a protective mechanism against allergic airway inflammation through controlling cell autophagy.</p></sec>