Cutaneous Biology Research Center, Department of Dermatology, and.
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
JCI Insight. 2016 Oct 6;1(16):e89362. doi: 10.1172/jci.insight.89362.
The challenge of translating findings from animal models to the clinic is well known. An example of this challenge is the striking effectiveness of neurokinin-1 receptor (NK-1R) antagonists in mouse models of inflammation coupled with their equally striking failure in clinical investigations in humans. Here, we provide an explanation for this dichotomy: Mas-related GPCRs (Mrgprs) mediate some aspects of inflammation that had been considered mediated by NK-1R. In support of this explanation, we show that conventional NK-1R antagonists have off-target activity on the mouse receptor MrgprB2 but not on the homologous human receptor MRGPRX2. An unrelated tripeptide NK-1R antagonist has dual activity on MRGPRX2. This tripeptide both suppresses itch in mice and inhibits degranulation from the LAD-2 human mast cell line elicited by basic secretagogue activation of MRGPRX2. Antagonists of Mrgprs may fill the void left by the failure of NK-1R antagonists.
将动物模型中的发现转化为临床应用面临着巨大的挑战。神经激肽-1 受体（NK-1R）拮抗剂在炎症的小鼠模型中表现出显著的效果，但在人体临床试验中却同样失败，这就是一个很好的例子。在这里，我们为这种双重性提供了一个解释：Mas 相关 G 蛋白偶联受体（Mrgprs）介导了一些被认为是由 NK-1R 介导的炎症反应。为了支持这一解释，我们表明传统的 NK-1R 拮抗剂对小鼠受体 MrgprB2 具有非靶点活性，但对同源的人类受体 MRGPRX2 没有活性。一种不相关的三肽 NK-1R 拮抗剂对 MRGPRX2 具有双重活性。这种三肽既能抑制小鼠的瘙痒，又能抑制由 MRGPRX2 的基本分泌激活引起的 LAD-2 人肥大细胞系脱颗粒。Mrgprs 的拮抗剂可能会填补 NK-1R 拮抗剂失败留下的空白。
