Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.

中文翻译：

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肥大细胞表达的 Mas 相关 G 蛋白偶联受体的激活驱动非组胺性瘙痒。

经典的瘙痒研究集中在免疫球蛋白 E (IgE) 介导的肥大细胞活化和组胺释放上。最近，Mas 相关 G 蛋白偶联受体 (Mrgpr) 家族的成员已被确定为肥大细胞受体，但它们在瘙痒中的作用尚不清楚。在这里，我们报告通过 Mrgprb2 激活肥大细胞在小鼠中引起非组胺能瘙痒，独立于 IgE-Fc epsilon RI (FcεRI)-组胺轴。与 IgE-FcεRI 刺激相比，肥大细胞的 Mrgprb2 激活在释放的物质（组胺、5-羟色胺和类胰蛋白酶）和激活的瘙痒感觉神经元的模式中都不同。在过敏性接触性皮炎 (ACD)（一种瘙痒性炎症性皮肤病）的多个临床前模型中，Mrgprb2 缺陷减少了瘙痒，并且在人 ACD 皮肤中肥大细胞数量和 PAMP1-20 浓度（人 Mrgprb2 同系物的激动剂，MRGPRX2）都增加了。这些发现表明，该途径可能代表了治疗抗组胺药无效的 ACD 和肥大细胞相关瘙痒症的治疗靶点。