Direct activation of aryl hydrocarbon receptor by benzo[a]pyrene elicits T‐helper 2‐driven proinflammatory responses in a mouse model of allergic dermatitis

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand‐dependent transcription factor that binds to various environmental chemicals and contributes to numerous toxicological effects. However, the direct effects of AhR on the development of allergic diseases are not fully understood. The main aim of this study was to elucidate the action of AhR in the development of cutaneous allergies. Initially, the potential for a direct relationship between AhR and the immune cells was investigated in vitro, using murine bone marrow‐derived dendritic cells, human epidermal keratinocytes, and the mixed leukocyte reaction assay. Benzo[a]pyrene (BaP) and 6‐formylindolo[3,2‐b]carbazole were used as selective ligands for the AhR. Pretreatment with BaP and/or 6‐formylindolo[3,2‐b]carbazole significantly induced cytokine release by activated keratinocytes and T‐cell proliferation, whereas interleukin‐12 production in bone marrow‐derived dendritic cells was reduced by AhR activation. To confirm the in vitro results, in vivo experiments were also performed in T‐helper (Th)2‐type hapten toluene‐2,4‐diisocyanate‐ and Th1‐type hapten dinitrochlorobenzene‐induced mouse models of allergic dermatitis. Mice were orally administered BaP at 48, 24 and 4 hours before the final allergen challenge. In the Th2 model, ear‐swelling response and scratching behavior were promoted by BaP exposure, which supported the observed significant increases in local cytokine secretion. The infiltration of helper T cells, B cells and dendritic cells into the auricular lymph node was significantly enhanced by BaP administration, although Th1‐type immune responses were not influenced by AhR activation. Our findings demonstrate that AhR activation directly activates keratinocytes and T cells, which leads to the exacerbation of Th2‐type cutaneous allergy.

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

“…The intact group indicates the background of normal BALB/c mice without both TDI and BaP. The doses of BaP (0.3 mg/kg and 1 mg/kg) used in the present study were selected according to those described by Tajima et al (2019), which did not lead to any systemic toxicity or immunosuppression. In addition, in a preliminary setting with a limited number of mice (three, 1 mg/kg BaP) conducted before the main study we found the same tendency as the main study, indicating the repeatability and reliability of the results from the present study.…”

“…However, no effect on dendritic cell activation was observed. In the Th2‐type mouse model, AhR activation promoted both inflammatory and pruritic responses, which indicated that AhR activation directly leads to exacerbation of Th2‐type cutaneous allergy (Tajima, Tajiki‐Nishino, Watanabe, & Fukuyama, 2019). Our results also suggested that other Th2‐driven immune disorders, such as asthma, would be affected by AhR activation as well.…”

Acute and subacute oral administration of mycotoxin deoxynivalenol exacerbates the pro-inflammatory and pro-pruritic responses in a mouse model of allergic dermatitis

“…Initially, we investigated the direct relationship between acute oral administration of DON and the development of Th2-type allergy in a highly reliable mouse model of TDIinduced allergic dermatitis, which has been widely used for evaluation of immunotoxicological effects of environmental chemicals including estrogen disruptors and Benzo [a] pyrene (Tajiki-Nishino et al 2018;Tajima et al 2019;Watanabe et al 2018). The biggest advantage of this model is that inflammatory and itch responses can be simultaneously observed; thus, we monitored pro-inflammatory and pro-pruritic responses to DON exposure in this model.…”

“…Single-cell suspensions were prepared from the LNs removed from each mouse and were used for flow cytometry and cytokine analysis (Makino et al 2019;Tajima et al 2019;Watanabe et al 2018). The total number of live cells was measured using Tali ® Image-Based Cytometer (Thermo Fisher Scientific, Inc., Kanagawa, Japan).…”

“…mBMDCs were obtained from the bone marrow of female BALB/c mice and generated by co-culturing with GM-CSF (PeproTech, Inc., Rocky Hill, NJ) for 8 days (Fukuyama et al 2015;Lutz et al 1999;Makino et al 2019;Tajiki-Nishino et al 2018;Tajima et al 2019;Watanabe et al 2018). Matured BMDCs (5 × 10 4 cells, containing > 90% CD11c-positive matured DCs.)…”