Protease-Activated Receptor-2 Decreased Zonula Occlidens-1 and Claudin-1 Expression and Induced Epithelial Barrier Dysfunction in Allergic Rhinitis

Background: Protease-activated receptor-2 (PAR-2)-modulated tight junctions (TJs) have been suggested to be involved in the pathogenesis of chronic inflammatory diseases. However, immunopathogenesis remains to be investigated among patients with allergic rhinitis (AR).

Objective: This study sought to investigate the role of PAR-2 in the modulation of epithelial barrier function and the expression of TJs in the nasal mucosa of AR patients.

Methods: The expression of TJs and PAR-2 of the nasal mucosa in AR patients and control subjects by immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting. In vitro, Primary human nasal epithelial cells (pHNECs) of AR patients were stimulated by Der p1 to analyze the correlation between PAR-2 and TJs expression. Der p1-induced pHNECs were treated with the PAR-2 agonist SLIGRL-NH2 and antagonist FSLLRY-NH2. Fluorescein isothiocyanate-dextran 4 kDa detection was employed as an indicator of epithelial permeability.

Results: Lower expression levels of TJs in the nasal epithelium of AR patients were observed in comparison with that in control subjects. The PAR-2 level was markedly increased following treatment with 1,000 ng/mL of Der p1 for 24 hours in a cellular model of AR. The expression of PAR-2 was increased in Der p1-induced pHNECs of AR patients and correlated inversely with zonula occlidens (ZO)-1 and claudin-1. Treatment with Der p1 further downregulated TJs expression and promoted an increased epithelial permeability in Der p1-induced pHNECs.

Conclusions: PAR-2 could downregulate the expression of ZO-1 and claudin-1, which is involved in epithelial barrier dysfunction in AR.

Keywords: Claudin-1; ZO-1; allergic rhinitis; primary human nasal epithelial cells; protease-activated receptor-2; tight junctions.