Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, MD, United States.
Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.
Front Immunol. 2022 Jul 22;13:964575. doi: 10.3389/fimmu.2022.964575. eCollection 2022.
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.
We sought to determine whether AhR specifically in type II alveolar epithelial cells (AT2) modulates allergic airway inflammation and its underlying mechanisms.
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 ( ). The effect of AhR on allergen-induced autophagy was examined by both and 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.
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 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 and are major autophagy-associated genes in AT2 cells that may contribute to the AhR-mediated cockroach allergen-induced airway inflammation and, subsequently, allergic asthma.
These results suggest that AhR in AT2 cells functions as a protective mechanism against allergic airway inflammation through controlling cell autophagy.
芳香烃受体（AhR）是一种配体激活的转录因子，被认为是免疫疾病的重要调节因子。我们之前已经表明 AhR 可以预防过敏性气道炎症。然而，其潜在机制仍未确定。
我们旨在确定 AhR 是否特异性地在 II 型肺泡上皮细胞（AT2）中调节过敏性气道炎症及其潜在机制。
通过在 AT2 细胞中条件性敲除 AhR 的哮喘小鼠模型研究 AhR 在气道炎症中的 AT2 细胞中的作用（）。通过 Western blot 和免疫荧光分析研究 AhR 对变应原诱导的自噬的影响。通过使用自噬抑制剂氯喹分析自噬在气道炎症中的作用。还通过 RNA 测序（RNA-seq）分析研究 AhR 调节的 AT2 细胞中的基因谱。
与野生型小鼠相比， 小鼠表现出变应原诱导的气道高反应性和气道炎症加剧，支气管肺泡灌洗液（BALF）中的 Th2 细胞因子水平升高。值得注意的是，与野生型小鼠相比， 小鼠的肺组织中观察到变应原诱导的自噬增加。进一步的分析表明，AhR-TGF-β1 功能轴在通过调节变应原诱导的细胞自噬来驱动过敏性气道炎症方面至关重要。此外，用自噬抑制剂氯喹抑制自噬可显著抑制蟑螂过敏原诱导的气道炎症、BALF 中的 Th2 细胞因子以及肺组织中自噬相关基因 LC3 和 Atg5 的表达。此外，RNA-seq 分析表明自噬是主要途径之一， 和 是 AT2 细胞中可能有助于 AhR 介导的蟑螂变应原诱导的气道炎症和随后的过敏性哮喘的主要自噬相关基因。
这些结果表明，AT2 细胞中的 AhR 通过控制细胞自噬作为预防过敏性气道炎症的保护机制。
