Kang Miran, Seo Yohan, Seo Ju Hee, Jeong Yeonsu, Jeon Hyejin, Jang Su-Myeong, Kim Chang-Hoon, Namkung Wan, Cho Hyung-Ju
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea.
College of Pharmacy, Yonsei Institute of Pharmaceutical Science, Yonsei University, Incheon, South Korea.
Int Forum Allergy Rhinol. 2025 Jul 11:e23623. doi: 10.1002/alr.23623.
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.
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.
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.
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.
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.
过敏性鼻炎（AR）和哮喘涉及Th1和Th2炎症途径之间的复杂相互作用。屋尘螨（HDM）激活蛋白酶激活受体2（PAR2）以触发炎症反应，但目前的治疗往往控制不足。
本研究旨在探讨选择性PAR2抑制对人鼻上皮（HNE）细胞以及AR和哮喘小鼠模型中Th1和Th2反应的影响。
我们使用原代HNE细胞和HDM诱导的小鼠模型（PAR2野生型[PAR2-wt]和敲除型[PAR2-ko]）研究了选择性PAR2抑制的作用。分析包括炎症信号通路、细胞因子谱、气道反应、组织病理学和转录组学。
在HNE细胞中，PAR2抑制可抑制Th2（白细胞介素[IL]-33、TSLP）和Th1（TNF-α、IL-6）炎症细胞因子，同时抑制钙动员和ERK/NF-κB信号级联反应。在PAR2-wt小鼠中，PAR2抑制剂治疗可降低HDM特异性免疫球蛋白E（IgE）、气道高反应性以及鼻和支气管组织中的过敏性炎症，与PAR2-ko小鼠的抗炎特征相符。批量RNA测序证实了炎症基因表达的全面抑制。
选择性PAR2抑制通过调节人气道上皮和小鼠模型中的Th1和Th2途径，有效减轻HDM诱导的过敏性炎症。我们认为PAR2可能是AR和哮喘的一个潜在靶点。
