Implications of MRGPRX2 in human and experimental cardiometabolic diseases.
Implications of MRGPRX2 in human and experimental cardiometabolic diseases.
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MRGPRX2 对人类和实验性心脏代谢疾病的影响。
DOI：
10.1038/nrcardio.2016.212
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Lerner EA
中科院分区：
文献类型：
--
作者：
Azimi E;Lerner EA
我们阅读了石国平等人的优秀评论。(Mast人类和实验性心脏代谢疾病中的细胞。国家心脏病研究所12，643-658; 2015）1，具有极大的兴趣。作者提出了神经肽在心脏和冠状动脉肥大细胞活化中的作用，特别关注P物质在这些过程中的作用。作者认为心血管事件和过敏之间存在关联。我们感兴趣的是介导瘙痒的基本机制。事实上，P物质和神经肽的作用及其与肥大细胞在瘙痒、过敏和炎性皮肤病中的相互作用与心脏代谢事件平行。基于先前的研究2，作者得出结论，P物质通过其同源受体神经激肽1（NK-1 R;也称为速激肽受体1）激活肥大细胞，诱导肥大细胞脱粒和随后的炎症。我们不同意NK-1 R参与P物质诱导的肥大细胞脱粒。大量研究表明，P物质诱导的肥大细胞脱粒和炎症特性是通过Mass相关G蛋白偶联受体（MRGPRs）MRGPRX 2介导的（参考文献3 4 5）。MRGPRX 2的小鼠直向同源物是Mrgprb 2（参考文献3）。物质P诱导的肥大细胞脱粒在Mrgprb 2 −/−小鼠的肥大细胞中减少3。我们已经确定，NK-1 R拮抗剂对小鼠Mrgprb 2具有脱靶抑制作用，但对人MRGPRX 2没有作用（参考文献4）。这一发现是至关重要的，因为几乎所有心脏代谢疾病领域的研究，包括Guo-Ping等人引用的研究，已经使用NK-1 R拮抗剂而不是Nk 1 r −/−（Tacr 1 −/−）小鼠来证明心脏和冠状动脉肥大细胞的P物质活化是NK-1 R依赖性的。NK-1 R拮抗剂长期以来一直被研究用于治疗与肥大细胞相关的炎症性疾病，例如偏头痛和哮喘。尽管在动物模型中有希望的临床前结果，但NK-1 R拮抗剂在炎性疾病的临床试验中无效6，7。鉴于P物质诱导的肥大细胞脱颗粒是通过MRGPRs介导的，并且NK-1 R拮抗剂抑制小鼠Mrgprb 2，但不抑制人MRGPRX 2，因此NK-1 R拮抗剂在治疗肥大细胞相关炎症方面的无效性不再令人惊讶。
We read the excellent Review by Guo-Ping Shi et al.(Mast cells in human and experimental cardiometabolic diseases. Nat. Rev. Cardiol. 12, 643–658; 2015) 1 with great interest. The authors proposed a role for neuropeptides in the activation of cardiac and coronary mast cells, with a specific focus on the role of substance P in these processes. The authors suggest an association between cardiovascular events and allergies. We are interested in basic mechanisms mediating itch. Indeed, a role for substance P and neuropeptides and their interaction with mast cells in the context of itch, allergy, and inflammatory skin disease is parallel to cardiometabolic events. On the basis of previous studies 2, the authors conclude that substance P activates mast cells via its cognate receptor, neurokinin 1 (NK-1R; also known as tachykinin receptor 1), to induce mast cell degranulation and subsequent inflammation. We respectfully disagree with involvement of NK-1R in substance P-induced mast cell degranulation. A plethora of studies have demonstrated that substance P-induced mast cell degranulation and inflammatory properties are mediated via a member of the Mas-related G-protein coupled receptors (MRGPRs), MRGPRX2 (Refs 3 4 5). The mouse orthologue of MRGPRX2 is Mrgprb2 (Ref. 3). Substance P-induced mast cell degranulation is diminished in mast cells from Mrgprb2−/− mice 3. We have identified that antagonists of NK-1R have an off-target inhibitory effect on mouse Mrgprb2, but not human MRGPRX2 (Ref. 4). This finding is critical, because almost all studies in the field of cardiometabolic disease, including the ones cited by Guo-Ping et al., have used NK-1R antagonists and not Nk1r−/−(Tacr1−/−) mice to demonstrate that substance P activation of cardiac and coronary mast cells is NK-1R-dependent.NK-1R antagonists have long been investigated for treating inflammatory conditions associated with mast cells, such as migraine and asthma. Despite promising preclinical results in animal models, NK-1R antagonists were ineffective in clinical trials of inflammatory diseases 6, 7. Given that substance P-induced mast cell degranulation is mediated via MRGPRs, and NK-1R antagonists inhibit mouse Mrgprb2, but not human MRGPRX2, the inefficacy of NK-1R antagonists in treating mast-cell-associated inflammation is no longer a surprise.
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影响因子：
64.8
作者：
McNeil, Benjamin D.;Pundir, Priyanka;Meeker, Sonya;Han, Liang;Undem, Bradley J.;Kulka, Marianna;Dong, Xinzhong
通讯作者：
Dong, Xinzhong
影响因子：
16.6
作者：
Reddy VB;Sun S;Azimi E;Elmariah SB;Dong X;Lerner EA
通讯作者：
Lerner EA
影响因子：
20.1
作者：
Bot, Ilze;de Jager, Saskia C. A.;Biessen, Erik A. L.
通讯作者：
Biessen, Erik A. L.
影响因子：
14.2
作者：
Fujisawa, Daisuke;Kashiwakura, Jun-ichi;Okayama, Yoshimichi
通讯作者：
Okayama, Yoshimichi
影响因子：
3.1
作者：
Ramalho R;Soares R;Couto N;Moreira A
通讯作者：
Moreira A