Polycyclic Aromatic Hydrocarbons promote Th22 polarization by reciprocally regulating IL-22 and IL- 17

Background: Pollution, including polyaromatic hydrocarbons (PAH), may contribute to increased prevalence of asthma. PAH bind to the Aryl hydrocarbon receptor (AhR), a transcription factor involved in Th17/Th22 polarization. IL-17 allows neutrophil recruitment and IL-22, tissue repair. Increased IL-17 and IL-22 productions have been associated with asthma. Objective: To evaluate if PAH might enhance, through their effects on AhR, Th17 and/or Th22 polarization and contribute to asthma. Methods: Activated peripheral blood mononuclear cells (PBMCs) from nonallergic nonasthmatic (NA) and allergic asthmatic (AA) subjects were incubated with PAH, and Th17/Th22 type cytokines and transcription factors evaluated by ELISA and Q-PCR respectively. Cytokine cell origin was determined by flow cytometry. The involvement of AhR and different kinases was evaluated using specific antagonists. Results: PBMCs from AA exhibited an increased Th17/Th22 profile compared with NA subjects. Diesel exhaust particle (DEP)-PAH and Benzo[a]Pyrene (B[a]P) stimulation further increased IL-22 but surprisingly decreased IL-17A production in both groups. Accordingly, Th17 transcription factors RORA and RORC were down regulated, whereas AhR target gene CYP1A1 was up-regulated in both groups. NOTCH was decreased only in AA patients. HAP-induced IL-22 production originated mainly from Th22 cells. The AhR antagonist reversed almost completely the effects of DEP-PAH, but only partially the effects of B[a]P, on IL-22/IL-17 reciprocal regulation. The kinases PI3K, JNK and ERK participated to the enhancing effect of B[a]P on IL-22 production, whereas p38 MAP kinase had an inhibitory effect. Conclusion: DEP-PAH- and B[a]P- induced excessive production of IL-22 in AA may contribute to the progression of airway remodeling. These apparently contradictory results were partly explained by the ligand used, the exogenous ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inducing functional T regulatory cells in mice and in humans whereas activation of AhR by the endogenous ligand FICZ boosted Th17 differentiation in mice but not in humans (12). Despite these discrepancies, these studies link environmental pollution to the Th17/Th22 program, opening intriguing possibilities regarding the potential of such factors to initiate or augment allergic asthma. Therefore, we hypothesized that DEP-PAH and some purified PAH previously shown to be involved in asthma, might enhance, through their effects on AhR, Th17 and/or Th22 polarization and contribute to allergic asthma. In the present study, we show for the first time to our knowledge, that DEP-PAH and Benzo-a-pyrene exacerbated Th22 polarization in stimulated mononuclear cells, particularly in allergic asthmatic patients, whereas Th17 polarization was inversely down regulated. The mechanisms of reciprocal regulation were partly dependent upon AhR, and also involved the MAP Kinase p38. Overall, these data show that IL-22 induction by B[a]P is dependent upon activation of AhR, PI3K ERK and JNK, and inhibition of p38 MAPK, whereas IL-17 inhibition is mediated partially by AhR and by p38 MAPK inhibition. Among these pathways AhR and p38 MAPK reciprocally regulate IL-17 and IL-22 production in response to PAH. Contrasting results that IL-22 inhibits IFN- γ -induced expression of proinflammatory chemokines in human bronchial epithelial cells and that the levels of IL-22 in the broncho-alveolar lavage fluid of asthmatic patients are inversely correlated with the levels of proinflammatory chemokines, suggesting a protective role of IL-22 in asthma (68). On the other hand, increase in the two cytokines has been associated with more severe asthma (24, 26, 28, 29), and IL-22 enhances the proliferation and migration of human airway smooth muscle cells (20, 21), suggesting that IL-22 may be involved in smooth muscle cell hyperplasia. Taken together, these studies suggest that limited production of IL-22 may play an inhibitory role on the bronchial cell infiltration but that prolonged secretion may also promote airway remodeling, a feature thought to explain the lack of corticosteroid sensitivity in severe asthmatics. In our study, PAH stimulation led to increased levels of IL-22 in NA subjects, which were further increased in AA patients. These data suggest that in asthmatic patients, PAH-induced excessive production of IL-22 may contribute to the progression of airway remodeling.