Mas-related G protein coupled receptor-X2: A potential new target for modulating mast cell-mediated allergic and inflammatory diseases.
Mas-related G protein coupled receptor-X2: A potential new target for modulating mast cell-mediated allergic and inflammatory diseases.
复制标题
DOI：
10.4172/2476-1966.1000115
复制
发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
H. Ali
中科院分区：
文献类型：
--
作者：
H. Ali
肥大细胞（MC）是组织驻留的免疫细胞，其在过敏性和炎症性疾病中的作用是众所周知的。除了高亲和力IgE受体（FcεRI）外，MC还表达许多G蛋白偶联受体（GPCR），这些受体是药物治疗的最常见靶点。神经激肽1受体（NK-1 R）在MC上表达，并参与小鼠中IgE和非IgE介导的反应。尽管NK-1 R拮抗剂在调节小鼠的实验性变态反应和炎症反应方面非常有效，但它们在人类中缺乏功效。本文综述了神经肽（NPs）通过NK-1 R和Mas相关G蛋白偶联受体B2（MrgprB 2）激活小鼠MC，而通过Mas相关G蛋白偶联受体X2（MRGPRX 2）激活人MC的最新研究结果。有趣的是，常规NK-1 R拮抗剂对小鼠MrgprB 2具有脱靶活性，但对人MRGPRX 2没有。这些结果表明，未能将NK-1 R拮抗剂的研究从体内小鼠研究转化为临床研究可能反映了其对人MRGPRX 2缺乏作用。MRGPRX 2区别于其他GPCR的独特特征是它被不同的配体组激活，所述配体组包括：神经肽、半胱氨酸蛋白酶、抗微生物肽和从活化的嗜酸性粒细胞释放的阳离子蛋白。因此，小分子MRGPRX 2特异性拮抗剂或中和抗体的开发可能为MC介导的过敏性和炎症性疾病的治疗提供新的靶点。
Mast cells (MCs) are tissue resident immune cells that are best known for their roles in allergic and inflammatory diseases. In addition to the high affinity IgE receptor (FcεRI), MCs express numerous G protein coupled receptors (GPCRs), which are the most common targets of drug therapy. Neurokinin 1 receptor (NK-1R) is expressed on MCs and contributes to IgE and non-IgE-mediated responses in mice. Although NK-1R antagonists are highly effective in modulating experimental allergic and inflammatory responses in mice they lack efficacy in humans. This article reviews recent findings that demonstrate that while neuropeptides (NPs) activate murine MCs via NK-1R and Mas related G protein coupled receptor B2 (MrgprB2), they activate human MCs via Mas-related G protein coupled receptor X2 (MRGPRX2). Interestingly, conventional NK-1R antagonists have off-target activity against mouse MrgprB2 but not human MRGPRX2. These findings suggest that the failure to translate studies with NK-1R antagonists from in vivo mouse studies to the clinic likely reflects their lack of effect on human MRGPRX2. A unique feature of MRGPRX2 that distinguishes it from other GPCRs is that it is activated by a diverse group of ligands that include; neuropeptides, cysteine proteases, antimicrobial peptides and cationic proteins released from activated eosinophils. Thus, the development of small molecule MRGPRX2-specific antagonists or neutralizing antibodies may provide new targets for the treatment of MC-mediated allergic and inflammatory diseases.