Selective PAR2 Inhibition Attenuates HDM-Induced Th1/Th2 Responses in Human Epithelial and Murine Models of Allergic Rhinitis and Asthma

Abstract

BackgroundAllergic rhinitis (AR) and asthma are involved in complex interactions between Th1 and Th2 inflammatory pathways. House dust mite (HDM) activates protease-activated receptor 2 (PAR2) to trigger inflammatory responses, but current treatments often provide inadequate control.ObjectiveThis study aimed to investigate the effects of selective PAR2 inhibition on Th1 and Th2 responses in human nasal epithelial (HNE) cells and murine models of AR and asthma.MethodsWe examined the effects of selective PAR2 inhibition using primary HNE cells and HDM-induced mouse models (PAR2-wild-type [PAR2-wt] and knockout [PAR2-ko]). Analyses included inflammatory signaling pathways, cytokine profiles, airway responses, histopathology, and transcriptomics.ResultsIn HNE cells, PAR2 inhibition suppressed Th2 (interleukin [IL]-33, TSLP) and Th1 (TNF-alpha, IL-6) inflammatory cytokines while inhibiting calcium mobilization and ERK/NF-kappa B signaling cascades. In PAR2-wt mice, treatment with the PAR2 inhibitor reduced HDM-specific Immunoglobulin E (IgE), airway hyperresponsiveness, and allergic inflammation in both nasal and bronchial tissues, matching the anti-inflammatory profile of PAR2-ko mice. Bulk RNA sequencing confirmed comprehensive suppression of inflammatory gene expression.ConclusionsSelective PAR2 inhibition effectively attenuates HDM-induced allergic inflammation by modulation of Th1 and Th2 pathways in human airway epithelium and murine models. We suggest that PAR2 can be a possible target for AR and asthma.