Activation of aryl hydrocarbon receptor by benzo[a]pyrene increases interleukin 33 expression and eosinophil infiltration in a mouse model of allergic airway inflammation

Abstract

We recently demonstrated that benzo[a]pyrene (BaP), the aryl hydrocarbon receptor (AhR) ligand, directly contributes to aggravation of cutaneous allergy in a mouse model of allergic dermatitis. The present study aimed to determine whether BaP-induced AhR activation results in development of airway inflammation. Initially, the potential for a direct relationship between BaP-induced AhR activation and airway inflammation was investigated in vivo, using a mouse model of type 2 helper T cell (Th2) hapten toluene-2,4-diisocyanate (TDI)-induced airway inflammation. Mice were orally administered BaP at 48, 24, and 4 h before the final allergen challenge. Oral administration of BaP showed a significant increase in lung inflammation and eosinophil infiltration. While expression of Th2 cytokines such as interleukin 4 (IL-4) and IL-13 was not affected by exposure to BaP, AhR activation significantly increased IL-33 expression. To confirm the in vivo results, in vitro experiments were performed using the human eosinophilic leukemia cell line (EOL-1), human bronchial epithelial cell line (BEAS-2B), and human lung adenocarcinoma epithelial cell line (A549). Results indicated that pre-treatment with BaP increased expression of IL-8 in house dust mite-activated EOL-1, BEAS-2B, and A549 cells. In addition, IL-33 levels in BEAS-2B cells were significantly increased after BaP exposure. Our findings indicated that BaP-induced AhR activation is involved in the pro-inflammatory response in respiratory allergy, and that this effect may be mediated by increased IL-33 expression and eosinophil infiltration.

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

“…Furthermore, we found that BaP exposure can activate AhR that subsequently leads to a promotion of Der f 1-induced oxidative stress and IL-25, IL-33, and TSLP release from the epithelium (29). Our findings were supported by some other studies showing that BaP can directly induce AhR activation that contributes to the pro-inflammatory response in respiratory allergy through enhancing IL-33 expression and eosinophil infiltration (17). In the current study, we extended to detect the BaP co-exposure-induced activation of AhR signaling by using AhR reporter plasmid (PGL3-6xDRE-GFP).…”

“…BaP is one of the ligands to AhR (17). We have previously shown that BaP can induce the expression of AhR and its major downstream gene CYP1A1 in 16HBECs (29).…”

“…Exposure to BaP alone has been shown to induce oxidative stress, bronchial epithelium injury, and inflammation (14)(15)(16). Mechanistically, BaP can directly activate aryl hydrocarbon receptor (AhR), induce IL-33 expression and eosinophil infiltration in a mouse model of allergic airway inflammation (17), and elicit T-helper 2-driven pro-inflammatory responses in a mouse model of allergic dermatitis (18). AhR, as a ligandactivated transcription factor, can be activated by small molecules in various diets, metabolites, microorganisms, and pollutants (19)(20)(21)(22)(23)(24) and plays an important role in the regulation of innate and adaptive immune responses (25)(26)(27)(28).…”

The Aryl Hydrocarbon Receptor in Asthma: Friend or Foe?

“…These data are in agreement with the ability of AhR to bind alarmin promoters and activate their transcription [30]. Interestingly, in vitro co-exposure of human epithelial cell lines to the HDM allergen Dermatophagoides farinae (Der f) and Benzo(a)pyrene (B(a)P), increases the expression of TSLP and IL-33 compared to cells stimulated with one or the other compound, effect also observed in vivo [26,27]. Moreover, Wang et al have shown that pre-incubation of epithelial cells with the AhR inhibitor CH223191 or transfection with a siRNA targeting the AhR decreases the expression of both cytokines, through effects on reactive oxygen species (ROS) production.…”

Genotoxic effect of simultaneous therapeutic exposure to polycyclic aromatic hydrocarbons and UV radiation

“…Polycyclic aromatic hydrocarbons (PAHs) represent a dangerous group of chemical mixtures (Błaszczyk & Mielżyńska‐Švach, 2017; Tajima, Tajiki‐Nishino, Watanabe, Kurata, & Fukuyama, 2020). Their genotoxic, mutagenic, carcinogenic, and immunotoxic effects have been described previously (IARC, 2010, 2020).…”