Epithelial AhR-NKX3-1-Senescence Axis Drives Barrier Function and Inflammation in Allergic Rhinitis

Allergic rhinitis (AR) is a common airway disease characterized by epithelial barrier dysfunction and Type 2 inflammation. Although the aryl hydrocarbon receptor (AhR) regulates mucosal immunity and epithelial homeostasis, its role in epithelial pathology in AR remains poorly defined. We sought to determine the contribution of AhR signaling to AR pathogenesis and to identify downstream mechanisms linking barrier dysfunction to Type 2 inflammation.

AhR expression and transcriptomic profiles were analyzed in nasal tissues from AR patients and controls. AhR-deficient (AhR^-/-) mice and CC10-CreER^TM; p16^f/f (p16^cKO) mice were used to assess the contributions of AhR signaling and p16-dependent epithelial senescence-associated programs to allergic inflammation and barrier integrity. Mechanistic pathways were interrogated using transcriptomic analysis, and pharmacologic modulation was evaluated by molecular docking and functional assays.

AhR expression was significantly increased in nasal epithelial cells from AR patients. AhR^-/- AR mice exhibited reduced Type 2 inflammation and preservation of epithelial barrier integrity. Transcriptomic analysis revealed enrichment of senescence-associated signatures in AR epithelium. AhR deficiency in primary epithelial cultures and AhR^-/- mice markedly attenuated epithelial senescence-associated programs. Consistently, p16^cKO AR mice showed reduced allergic inflammation and improved barrier function. Mechanistically, NKX3-1 was identified as an AhR-interacting regulator in cell-cycle arrest. Gain- and loss-of-function studies demonstrated that NKX3-1 contributes to allergen-induced epithelial senescence-associated programs. Finally, curcumin attenuated epithelial senescence-associated phenotypes with concomitant suppression of AhR and NKX3-1 expression.

These findings support a context-dependent model in which AhR-NKX3-1-associated epithelial senescence programs contribute to barrier dysfunction and allergic inflammation in AR.