Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
Department of Nursing, Huashan Hospital, Fudan University, Shanghai, China.
Skin Res Technol. 2024 Feb;30(2):e13588. doi: 10.1111/srt.13588.
Prurigo nodularis (PN) is a chronic inflammatory skin disorder that is characterized by extremely itchy nodules. Proadrenomedullin N-terminal 20 (PAMP) activates mast cell degranulation via Mas-related G protein-coupled receptor X2 (MRGPRX2), which is associated with pruritus in allergic contact dermatitis. However, the mechanisms underlying the action of PAMP and MRGPRX2 in PN remain unclear.
To determine the role of PAMP-induced mast cell activation via MRGPRX2 (mouse homologous Mrgprb2) in PN.
The expression of PAMP and the number of MRGPRX2-expressing mast cells in the skin biopsies of patients with PN, atopic dermatitis (AD), and healthy participants were analyzed using immunohistochemistry and immunofluorescence, respectively. The biphasic response of PAMP9-20 mediated by Mrgprb2 in mouse peritoneal mast cells (PMC) was validated in vitro using qRT-PCR, ELISA, flow cytometry, and siRNA techniques.
PAMP expression and the number of MRGPRX2+ mast cells in lesional PN skin, but not in AD, were elevated compared to healthy skin. PAMP9-20 mediates the immediate and delayed phase responses of PMC, such as degranulation, histamine and β-hexosaminidase release, and secretion of inflammatory factors such as CCL2, TNF-α, and GM-CSF. These effects were inhibited when Mrgprb2 expression was silenced. Silencing Mrgprb2 did not affect the biphasic response of PMC that was induced by IgE-FcεRI activation.
The results show that PAMP mediates mouse mast cell activation via Mrgprb2, which may be involved in the pathogenesis of PN. The PAMP/ Mrgprb2 pathway, independent of classical IgE signaling, could be developed as a candidate drug target for treating PN.
结节性痒疹（PN）是一种慢性炎症性皮肤病，其特征为极度瘙痒的结节。前肾上腺髓质素 N 端 20 肽（PAMP）通过与变应性接触性皮炎瘙痒相关的 Mas 相关 G 蛋白偶联受体 X2（MRGPRX2）激活肥大细胞脱颗粒。然而，PAMP 和 MRGPRX2 在 PN 中的作用机制尚不清楚。
确定 PAMP 通过 MRGPRX2（小鼠同源 Mrgprb2）诱导肥大细胞激活在 PN 中的作用。
采用免疫组化和免疫荧光法分别分析 PN 患者、特应性皮炎（AD）患者和健康对照者皮肤活检组织中 PAMP 的表达和 MRGPRX2 表达的肥大细胞数量。体外采用 qRT-PCR、ELISA、流式细胞术和 siRNA 技术验证 PAMP9-20 对小鼠腹膜肥大细胞（PMC）的双相反应。
与健康皮肤相比，PN 皮损皮肤中 PAMP 表达和 MRGPRX2+肥大细胞数量升高，但 AD 皮损皮肤中无此变化。PAMP9-20 介导 PMC 的即刻和迟发型反应，如脱颗粒、组胺和β-己糖胺酶释放以及 CCL2、TNF-α 和 GM-CSF 等炎症因子的分泌。当沉默 Mrgprb2 表达时，这些作用受到抑制。沉默 Mrgprb2 不影响 IgE-FcεRI 激活诱导的 PMC 双相反应。
结果表明，PAMP 通过 Mrgprb2 介导小鼠肥大细胞激活，这可能与 PN 的发病机制有关。PAMP/MRGPRX2 通路，不依赖于经典 IgE 信号，可作为治疗 PN 的候选药物靶点。
