Benzo(a)pyrene Enhanced Dermatophagoides Group 1 (Der f 1)-Induced TGFβ1 Signaling Activation Through the Aryl Hydrocarbon Receptor-RhoA Axis in Asthma.

Eryi Wang,Peisong Gao,Liteng Yang,Shau-Ku Huang,Zhigang Liu,Shehar B Bhatti,Danh C Do,Xiaojun Xiao,Wei Tu,Damo Xu,Pingchang Yang,Xizhuo Sun

doi:10.3389/fimmu.2021.643260

Abstract

We have previously demonstrated that benzo(a)pyrene (BaP) co-exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1-induced airway inflammation. The underlying mechanism, however, remains undetermined. Here we investigated the molecular mechanisms underlying the potentiation of BaP exposure on Der f 1-induced airway inflammation in asthma. We found that BaP co-exposure potentiated Der f 1-induced TGFβ1 secretion and signaling activation in human bronchial epithelial cells (HBECs) and the airways of asthma mouse model. Moreover, BaP exposure alone or co-exposure with Der f 1-induced aryl hydrocarbon receptor (AhR) activity was determined by using an AhR-dioxin-responsive element reporter plasmid. The BaP and Der f 1 co-exposure-induced TGFβ1 expression and signaling activation were attenuated by either AhR antagonist CH223191 or AhR knockdown in HBECs. Furthermore, AhR knockdown led to the reduction of BaP and Der f 1 co-exposure-induced active RhoA. Inhibition of RhoA signaling with fasudil, a RhoA/ROCK inhibitor, suppressed BaP and Der f 1 co-exposure-induced TGFβ1 expression and signaling activation. This was further confirmed in HBECs expressing constitutively active RhoA (RhoA-L63) or dominant-negative RhoA (RhoA-N19). Luciferase reporter assays showed prominently increased promoter activities for the AhR binding sites in the promoter region of RhoA. Inhibition of RhoA suppressed BaP and Der f 1 co-exposure-induced airway hyper-responsiveness, Th2-associated airway inflammation, and TGFβ1 signaling activation in asthma. Our studies reveal a previously unidentified functional axis of AhR–RhoA in regulating TGFβ1 expression and signaling activation, representing a potential therapeutic target for allergic asthma.

Highlights

Air pollution, especially exposure to particulate matter, is one of the major risk factors for the increased prevalence of childhood asthma worldwide [1]
Der f 1 exposure can induce Transforming growth factor β1 (TGFβ1) production, which was further potentiated by BaP co-exposure in human bronchial epithelial cell (16HBEC) (Figure 1C)
We further investigated whether active aryl hydrocarbon receptor (AhR) plays a role in TGFβ1 release from airway epithelial cells. 16HBECs were pre-treated with AhR antagonist CH223191 and exposed to either BaP or Der f 1 or their combination for 24 h

Summary

Introduction

Especially exposure to particulate matter, is one of the major risk factors for the increased prevalence of childhood asthma worldwide [1]. High levels of particulate matter [i.e., diesel exhaust particles (DEP)] can enhance the risk of atopic sensitization and exacerbation of asthma [2,3,4]. Prenatal exposure to DEP or DEP-derived polycyclic aromatic hydrocarbons (PAHs) is associated with atopic sensitization, early childhood wheeze, and asthma [5, 6]. DEP co-exposure with house dust mite can exacerbate allergic sensitization and induce key features of asthma mouse models [7,8,9,10,11]. The causal relationship and underlying molecular mechanisms are poorly characterized

Methods

Results

Conclusion