College of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, China.
School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory for Disease Prevention and Control and Health Promotion of Shaanxi Province, Xi'an, Shaanxi 710061, China.
Int Immunopharmacol. 2023 Apr;117:110003. doi: 10.1016/j.intimp.2023.110003. Epub 2023 Mar 15.
Allergic contact dermatitis (ACD) is one of the most common dermatoses, which has high disease burden and quality of life impairment. Anti-histamine is not effective in a part of the ACD patients. Thus, the discovery of novel antipruritic therapy is of highly demand.
In this study, we investigated the anti-pruritic effects of rosmarinic acid (RA) and explored the underlying mechanism.
SPF Balb/c mice were randomly divided into control group, ACD model group, RA group (1.0 mg/kg) and loratadine (LORA) group (1.5 mg/kg). Back epidermal thickness was recorded. H&E staining was used for pathological observation. Mast cell degranulation was assessed by toluidine blue staining. ELISA assay was employed to detect cytokines levels. Cortistatin-14 (CST-14) and Mas-related G protein-coupled receptor X2 (MRGPRX2) expression was detetcted by RT-PCR and western blot. Molecular docking assay was used to predict the affinity of RA and MRGPRX2. Surface plasmon resonance (SPR) assay was used to verify structure affinity of RA and MRGPRX2.
RA treatment significantly decreased epidermal keratinization and inflammatory cell infiltration in ACD mouse model. Administration of RA significantly reduced secretion of histamine, IL-13, and mRNA expression of CST-14. Furthermore, RA treatment increased mRNA expression of MRGPRX2. In addition, Molecular docking results predict that RA has a good affinity with MRGPRX2. RA displayed a structure affinity (K = 8.89 × 10) with MRGPRX2 by SPR. RA inhibited CST-14 and Compound 48/80 (C48/80)-induced mast cell activation via MRGPRX2-PLCγ1-PKC-NF-κB signaling pathway.
RA exhibits anti-pruritic and anti-inflammatory effects in ACD mice by inhibiting MRGPRX2-PLCγ1-PKC-NF-κB signaling pathway. RA might emerge as a potential drug for the treatment of pruritus and skin inflammation in the setting of ACD.
变应性接触性皮炎（ACD）是最常见的皮肤病之一，具有较高的疾病负担和生活质量受损。部分 ACD 患者对抗组胺治疗无效。因此，新型止痒疗法的发现需求很高。
本研究旨在探讨迷迭香酸（RA）的止痒作用及其机制。
将 SPF Balb/c 小鼠随机分为对照组、ACD 模型组、RA 组（1.0mg/kg）和氯雷他定（LORA）组（1.5mg/kg）。记录背部表皮厚度。采用 H&E 染色观察病理变化。甲苯胺蓝染色评估肥大细胞脱颗粒。采用 ELISA 法检测细胞因子水平。采用 RT-PCR 和 Western blot 检测皮质抑素 14（CST-14）和 Mas 相关 G 蛋白偶联受体 X2（MRGPRX2）的表达。采用分子对接预测 RA 与 MRGPRX2 的亲和力。采用表面等离子体共振（SPR）验证 RA 与 MRGPRX2 的结构亲和力。
RA 治疗可显著降低 ACD 小鼠模型的表皮角化和炎症细胞浸润。RA 治疗可显著减少组胺、IL-13 的分泌和 CST-14 的 mRNA 表达。此外，RA 治疗可增加 MRGPRX2 的 mRNA 表达。此外，分子对接结果预测 RA 与 MRGPRX2 具有良好的亲和力。SPR 结果显示 RA 与 MRGPRX2 的结构亲和力（K=8.89×10）。RA 通过 MRGPRX2-PLCγ1-PKC-NF-κB 信号通路抑制 CST-14 和化合物 48/80（C48/80）诱导的肥大细胞活化。
RA 通过抑制 MRGPRX2-PLCγ1-PKC-NF-κB 信号通路，在 ACD 小鼠中表现出止痒和抗炎作用。RA 可能成为治疗 ACD 瘙痒和皮肤炎症的潜在药物。
