Zhou Hongmei, Zhao Xi, Ye Dan, Zhao Qiang, Yang Mengyao, Wang Zhaoyang, Wang Li, Wang Chao, Geng Songmei, Zeng Weihui, Wang Zhao
Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Laboratory Medicine, Affiliated Hospital of Yan'an University, Yan'an, China.
Eur J Pharmacol. 2025 Nov 5;1006:178189. doi: 10.1016/j.ejphar.2025.178189. Epub 2025 Sep 24.
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.
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.
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.
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.
由非IgE介导的肥大细胞（MC）活化引起的类过敏反应导致了多种皮肤病，其中 Mas相关G蛋白偶联受体X2（MRGPRX2）被认为是关键受体。水杨酸（SA）长期以来在皮肤科作为具有抗炎特性的角质剥脱剂应用，但它在与MRGPRX2相关的类过敏反应中的作用仍不清楚。
在体内，采用结合伊文思蓝染料外渗试验的小鼠皮肤类过敏反应模型，用于C57BL/6小鼠。在体外，用人皮肤来源的MC和LAD2细胞，用MRGPRX2激动剂化合物48/80（c48/80）和P物质（SP）进行激活。通过β-己糖胺酶释放和钙内流试验评估脱颗粒和钙内流。RT-qPCR定量mRNA表达，而激酶磷酸化和活性氧（ROS）水平分别使用蛋白质免疫印迹法和流式细胞术进行评估。通过流式细胞术和免疫荧光分析MRGPRX2细胞表面表达。
在体内，SA显著减轻了MRGPRX2介导的皮肤水肿和伊文思蓝染料外渗。在体外，SA抑制了人皮肤来源的MC和LAD2细胞中的MC脱颗粒和钙内流。它还抑制了MRGPRX2激活后炎性细胞因子IL-4、IL-8和TNF-α的mRNA表达。SA预处理降低了ROS水平并抑制了细胞外信号调节激酶（ERK）磷酸化。此外，长时间暴露于SA会下调MRGPRX2 mRNA和细胞表面表达。
SA对MRGPRX2介导的类过敏反应具有双相抑制作用。短期SA治疗可抑制MC脱颗粒和细胞因子产生，而长期治疗则进一步降低MRGPRX2表达，突出了SA对与MRGPRX2相关的皮肤病的治疗潜力。
