Protease-activated receptor 2 and IL-13Rα1 activation is linked to eosinophilic chronic rhinosinusitis.

Background: Protease-activated receptor 2 (PAR-2) and IL-13 receptor α1 (IL-13Rα1) play major roles in type 2 inflammation. However, most of the literature was limited to allergic asthma.

Objective: This study examined how these receptors contribute to upper respiratory tract inflammation and explored potential therapeutic targets in patients with eosinophilic chronic rhinosinusitis (eCRS).

Methods: Using protein interaction analysis, animal experiments, and human tissue samples, we assessed the effects of exposure to house dust mite (HDM) allergen on PAR-2 and IL-13Rα1 activation and inflammatory markers, as well as the impact of the PAR-2 antagonist GB88. A fluorescent multiplex staining kit was used along with specific antibodies to label and detect proteins in the immunofluorescence tissue samples.

Results: Close relationship between PAR-2 (F2RL1), SPI-1, IL-13Rα1, and RNASE2 (EDN) was noted in protein interaction analysis. HDM exposure significantly activated PAR-2 and IL-13Rα1 in nasal epithelial cells, leading to Th2 cytokine release (IL-25, IL-33 & TSLP) and elevation of eosinophil proteins (ECP and EDN) that intensify upper respiratory tract inflammation. The PAR-2 antagonist GB88 reduced HDM allergen-induced PAR-2 and IL-13Rα1 expression, STAT-6 phosphorylation, and eosinophil infiltration, and decreased inflammatory markers. PAR2/SPI-1/ IL-13Rα1 was validated in IHC and IF analysis of human chronic rhinosinusitis specimens.

Conclusion: The PAR-2/IL-13Rα1 pathway is a promising target for treating upper respiratory tract inflammation. PAR-2 inhibitors could reduce inflammation and improve the outcomes of upper respiratory tract diseases, like eCRS.