Aryl Hydrocarbon Receptor is Essential in the Control of Lung Club Cell Homeostasis

Background: Club cells play an important role in maintaining lung homeostasis and aryl hydrocarbon receptor (AhR) is known to be important in xenobiotic metabolism, but its role in regulating club cells is currently unknown. Methods: To this end, mice with club cell-specific AhR deficiency were generated and evaluated in a model of antigen (ovalbumin, OVA)-induced airway inflammation for the number of infiltrating inflammatory cells, the levels of cytokines and CC10 and Notch signaling by standard methods. Results: After OVA sensitization and challenge, Scgb1a1-Cre; Ahr(flox/flox) mice showed aggravated levels of pulmonary inflammation with increased levels of inflammatory cells and cytokines 1 day after challenge as compared to those seen in their littermate controls, but in contrast to the littermate controls, no significant change in the levels of CC10 and SP-D was noted in Scgb1a1-Cre; Ahr(flox/flox) mice. Surprisingly, 7 days after the challenge, while, as expected, wild-type mice recovered from acute inflammation, significantly increased lymphocytic infiltration was noted in Scgb1a1-Cre; Ahrflox/flox mice, suggesting their defective mechanism of recovery. Mechanistically, this was due, in part, to the decreased Notch1 signaling and expression of its downstream gene, HES5, while AhR was shown to positively regulate Notch1 expression via its transactivating activity targeting the xenobiotic response element in the promoter region of Notch1 gene. Conclusion: Under the condition of pulmonary inflammation, AhR is critical in controlling lung club cell homeostasis via targeting Notch1 signaling and the generation of anti-inflammatory mediators.