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Published on: September 22, 2023
Selective PAR2 Inhibition Attenuates HDM-Induced Th1/Th2 Responses in Human Epithelial and Murine Models of Allergic
Miran Kang1, Yohan Seo2,3, Ju Hee Seo1
1Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea.
Background:
Allergic 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.
Objective:
This 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.
Methods:
We 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.
Results:
In HNE cells, PAR2 inhibition suppressed Th2 (interleukin [IL]-33, TSLP) and Th1 (TNF-α, IL-6) inflammatory cytokines while inhibiting calcium mobilization and ERK/NF-κB 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.
Conclusions:
Selective 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.
Insights
Selective protease-activated receptor 2 (PAR2) inhibition reduces allergic inflammation in airway diseases like allergic rhinitis and asthma. This approach modulates key inflammatory pathways, offering a potential new therapeutic target.
Area of Science:
- Immunology
- Respiratory Medicine
- Pharmacology
Background:
- Allergic rhinitis (AR) and asthma involve complex Th1/Th2 inflammatory interactions.
- House dust mite (HDM) triggers inflammation via protease-activated receptor 2 (PAR2).
- Current AR and asthma treatments offer inadequate symptom control.
Purpose of the Study:
- To investigate selective PAR2 inhibition effects on Th1/Th2 responses.
- To evaluate PAR2 inhibition in human nasal epithelial (HNE) cells and mouse models of AR and asthma.
Main Methods:
- Utilized primary HNE cells and HDM-induced mouse models (PAR2-wild-type and knockout).
- Analyzed inflammatory signaling, cytokine profiles, airway responses, histopathology, and transcriptomics.
- Assessed PAR2 inhibitor effects on calcium mobilization and ERK/NF-κB pathways.
Main Results:
- PAR2 inhibition suppressed Th2 (IL-33, TSLP) and Th1 (TNF-α, IL-6) cytokines in HNE cells.
- In mice, PAR2 inhibition reduced HDM-specific IgE, airway hyperresponsiveness, and allergic inflammation.
- Transcriptomics confirmed broad suppression of inflammatory gene expression.
Conclusions:
- Selective PAR2 inhibition effectively reduces allergic inflammation in airway epithelium.
- PAR2 inhibition modulates both Th1 and Th2 pathways.
- PAR2 presents a potential therapeutic target for allergic rhinitis and asthma.
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