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

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.

Epithelial Aryl Hydrocarbon Receptor Protects From Mucus Production by Inhibiting ROS-Triggered NLRP3 Inflammasome in Asthma

“…To investigate the molecular mechanisms underlying the cockroach allergen induced Muc5ac expression, we specifically focused on AhR signaling pathway. Our recent studies have demonstrated that AhR is critical in BaP co-exposure with Der f 1-induced IL-25, IL-33, and TSLP release from airway epithelial cells ( 32 , 33 ). Furthermore, AhR signaling has been shown to regulate the BaP-induced Muc5ac overexpression in airway epithelial cells ( 34 , 35 ).…”

“…Recently, AhR has been associated with asthma ( 22 – 26 ) and shown to mediate environmental pollutant-enhanced allergic lung inflammation ( 23 , 27 – 29 ), ROS-dependent degranulation and activation of mast cells ( 30 , 31 ). We have recently demonstrated that benzo(a)pyrene (BaP, a ubiquitous air pollutant) co-exposure with Der f 1 (a common allergen to human) induced the activation of AhR signaling, which subsequently regulated the co-exposure-induced airway epithelial cell oxidative stress and cytokine release ( 32 , 33 ). Importantly, several studies have suggested that the BaP-induced activation of AhR signaling regulates Muc5ac overexpression in airway epithelial cells ( 34 , 35 ).…”

Identifying Potential Diagnostic Genes for Diabetic Nephropathy Based on Hypoxia and Immune Status

“…Ras homolog gene family member (RhoA) plays an essential role in the cytoskeleton, maintaining cell morphology, cell migration, and smooth muscle cell contraction. 41 It also plays a key role in many biological activities, such as smooth muscle cell proliferation, cell adhesion, platelet aggregation, contact inhibition, growth, and apoptosis; 42 RhoA /ROCK signaling pathway is co-involved with its downstream effector Rho-associated protein kinase (ROCK), which has been shown to activate when exposed to diabetic kidney cells, 43 some studies have found that FASUDIL treatment inhibits RhoA/ROCK activation and NF-κB nuclear translocation significantly reduces the levels of renal cell adhesion molecule-1 and TGF-β1 proteins 44 and attenuates NF-κB-inflammatory gene upregulation-mediated DN progression. 45 , 46 CDKN1B, also known as cyclin-dependent kinase inhibitor 1B (P27, KIP1), is highly diagnostic in this study of renal tubular injury caused by diabetes, and G1 cells are now thought to be associated with growth inhibition or hypertrophy, cell cycle transitions can be blocked by the cyclin-dependent kinase reactive protein/kinase inhibitor (CIP/Kip) family of cyclin-dependent kinase inhibitors (CKIS: P21, P27, and P57).…”

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

“…Indeed, AhR has been associated with environmental pollutant-induced allergic airway inflammation (18,(23)(24)(25) and reactive oxygen species (ROS)-dependent mast cell degranulation and activation (26,27). Our previous findings have suggested that benzo(a)pyrene (BaP, a ubiquitous air pollutant) co-exposure with Der f 1 (a common allergen to human) exacerbated AhR signaling pathway that regulates the co-exposure-induced airway epithelial cell oxidative stress and cytokine release (28,29). Furthermore, our recent study demonstrated that epithelial AhR is essential in protecting against cockroach allergeninduced ROS generation, NLRP3 inflammasome activation, and Muc5ac expression (30).…”