Role of IL‐13Rα2 in modulating IL‐13‐induced MUC5AC and ciliary changes in healthy and CRSwNP mucosa

Background The IL‐13 receptor α2 (IL‐13Rα2) is a receptor for IL‐13 which has conflicting roles in mediating IL‐13 responses in the lower airway, with little known about its impact on upper airway diseases. We sought to investigate the expression of IL‐13 receptors, IL‐13Rα1 and IL‐13Rα2, in chronically inflamed nasal epithelium, and explore IL‐13‐induced signaling pathways in an in vitro model of human nasal epithelial cells (hNECs). Methods The protein and mRNA expression levels of IL‐13 and its receptors in nasal biopsies of patients with nasal polyps (NP) and healthy controls were evaluated. We investigated goblet cell stimulation with mucus hypersecretion induced by IL‐13 (10 ng/mL, 72 hours) treatment in hNECs using a pseudostratified epithelium in air‐liquid interface (ALI) culture. Results There were significant increases in IL‐13, IL‐13Rα1, and IL‐13Rα2 mRNA and protein levels in NP epithelium with healthy controls as baseline. MUC5AC mRNA positively correlated with IL‐13Rα2 (r = .5886, P = .002) but not with IL‐13Rα1 in primary hNECs. IL‐13 treatment resulted in a significant increase in mRNA and protein levels of IL‐13Rα2 only in hNECs. IL‐13 treatment induced an activation of extracellular signal‐regulated kinases (ERK)1/2 and an upregulation of C‐JUN, where the IL‐13‐induced effects on hNECs could be attenuated by ERK1/2 inhibitor (50 μmol/L) or dexamethasone (10−4‐10−7 mol/L) treatment. Conclusions IL‐13Rα2 has a potential role in IL‐13‐induced MUC5AC and ciliary changes through ERK1/2 signal pathway in the nasal epithelium. IL‐13Rα2 may contribute to airway inflammation and aberrant remodeling which are the main pathological features of CRSwNP. The increase in IL‐13Rα2 with IL‐13 treatment activates ERK1/2, which is associated with IL‐13‐induced MUC5AC upregulation and impaired ciliary function in hNECs. IL‐13‐induced effects on hNECs could be attenuated either by ERK1/2 inhibitor PD98059 or by dexamethasone treatment. IL‐13Rα2 has a potential role in airway inflammation and aberrant remodeling.