Salicylic acid inhibits Mas-related G protein-coupled receptor X2-mediated mast cell 2 activation and mitigates cutaneous pseudo-allergic reactions

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology Pub Date : 2025-09-24 DOI:10.1016/j.ejphar.2025.178189

Hongmei Zhou , Xi Zhao , Dan Ye , Qiang Zhao , Mengyao Yang , Zhaoyang Wang , Li Wang , Chao wang , Songmei Geng , Weihui Zeng , Zhao Wang

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引用次数: 0

Abstract

Background

Pseudo-allergic reactions mediated by non-IgE mast cells (MCs) activation contribute to various dermatological conditions, with Mas-related G protein-coupled receptor X2 (MRGPRX2) recognized as a key receptor. Salicylic acid (SA) has long been applied in dermatology as a peeling agent with anti-inflammatory properties, but its role in MRGPRX2-associated pseudo-allergic responses remains unclear.

Methods

In vivo, a murine skin pseudo-allergic reaction model combined with Evans blue dye extravasation assay was employed in C57BL/6 mice. In vitro, human skin-derived MCs and LAD2 cells were activated with MRGPRX2 agonists compound 48/80 (c48/80) and substance P (SP). Degranulation and calcium influx were assessed via β-hexosaminidase release and calcium influx assays. RT-qPCR quantified mRNA expression, while kinase phosphorylation and reactive oxygen species (ROS) levels were evaluated using western blotting and flow cytometry, respectively. MRGPRX2 cell surface expression was analyzed by flow cytometry and immunofluorescence.

Results

In vivo, SA significantly reduced MRGPRX2-mediated skin edema and Evans blue dye extravasation. In vitro, SA inhibited MC degranulation and calcium influx in both human skin-derived MCs and LAD2 cells. It also suppressed the mRNA expression of inflammatory cytokines IL-4, IL-8, and TNF-α following MRGPRX2 activation. SA pre-treatment reduced ROS levels and inhibited extracellular signal-regulated kinase (ERK) phosphorylation. Additionally, prolonged SA exposure downregulated both MRGPRX2 mRNA and cell surface expression.

Conclusions

SA demonstrates a dual-phase inhibitory effect on MRGPRX2-mediated pseudo-allergic reactions. Short-term SA treatment suppresses MC degranulation and cytokine production, whereas long-term treatment further reduces MRGPRX2 expression, highlighting the therapeutic potential of SA for MRGPRX2-associated dermatological disorders.

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水杨酸抑制mass相关G蛋白偶联受体x2介导的肥大细胞2活化并减轻皮肤假性过敏反应

背景：非ige肥大细胞（MCs）激活介导的假性过敏反应可导致多种皮肤病，而mass相关的G蛋白偶联受体X2 （MRGPRX2）被认为是一个关键受体。水杨酸（Salicylic acid， SA）作为一种具有抗炎特性的脱皮剂长期应用于皮肤科，但其在mrgprx2相关的假性过敏反应中的作用尚不清楚。方法：在体内采用小鼠皮肤假性过敏反应模型，结合Evans蓝染料外渗试验。体外，MRGPRX2激动剂化合物48/80 （c48/80）和P物质（SP）激活人皮肤源性MCs和LAD2细胞。通过β-己糖氨酸酶释放和钙内流测定来评估脱颗粒和钙内流。RT-qPCR量化mRNA表达，western blotting和流式细胞术分别评估激酶磷酸化和活性氧（ROS）水平。流式细胞术和免疫荧光法检测MRGPRX2细胞表面表达。结果：在体内，SA可显著减少mrgprx2介导的皮肤水肿和Evans蓝染料外渗。在体外，SA抑制人皮肤源性MCs和LAD2细胞的MC脱颗粒和钙内流。它还抑制MRGPRX2激活后炎症细胞因子IL-4、IL-8和TNF-α的mRNA表达。SA预处理降低ROS水平，抑制细胞外信号调节激酶（ERK）磷酸化。此外，长时间暴露于SA可下调MRGPRX2 mRNA和细胞表面表达。结论：SA对mrgprx2介导的假性过敏反应具有双期抑制作用。短期SA治疗抑制MC脱颗粒和细胞因子的产生，而长期治疗进一步降低MRGPRX2的表达，突出了SA对MRGPRX2相关皮肤病的治疗潜力。

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来源期刊

European journal of pharmacology 医学-药学

CiteScore

9.00

自引率

0.00%

发文量

572

审稿时长

34 days

期刊介绍： The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems. The scope includes: Behavioural pharmacology Neuropharmacology and analgesia Cardiovascular pharmacology Pulmonary, gastrointestinal and urogenital pharmacology Endocrine pharmacology Immunopharmacology and inflammation Molecular and cellular pharmacology Regenerative pharmacology Biologicals and biotherapeutics Translational pharmacology Nutriceutical pharmacology.