Protease-activated receptor 2 and interleukin-13 receptor α1 activation is linked to eosinophilic chronic rhinosinusitis.

BACKGROUND

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

OBJECTIVE

To evaluate ways these receptors contribute to upper respiratory tract inflammation and to explore potential therapeutic targets in patients with eosinophilic chronic rhinosinusitis.

METHODS

Using protein interaction analysis, animal experiments, and human tissue samples, we assessed the effects of exposure to house dust mite allergen on PAR-2 and IL-13Rα1 activation and inflammatory markers, and 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

A close relationship among PAR-2 (coagulation factor II receptor-like 1), SPI-1, IL-13Rα1, and RNASE2 (eosinophil-derived neurotoxin) was noted in protein interaction analysis. House dust mite exposure significantly activated PAR-2 and IL-13Rα1 in nasal epithelial cells, leading to T2 cytokine release (IL-25, IL-33, and thymic stromal lymphopoietin) and elevation of eosinophil proteins (eosinophil cationic protein and eosinophil-derived neurotoxin) that intensify upper respiratory tract inflammation. The PAR-2 antagonist GB88 reduced house dust mite allergen-induced PAR-2 and IL-13Rα1 expression, signal transducer and activator of transcription 6 phosphorylation, and eosinophil infiltration, and decreased inflammatory markers. PAR-2/SPI-1/IL-13Rα1 was validated in immunohistochemistry and immunofluorescence 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, such as eosinophilic chronic rhinosinusitis.