Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; College of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, China.
College of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, China.
Int Immunopharmacol. 2023 May;118:110034. doi: 10.1016/j.intimp.2023.110034. Epub 2023 Mar 21.
Mas-related G protein-coupled receptor X2 (MRGPRX2) plays a vital role in mast cells (MCs) degranulation and pseudo-allergic reactions. Leukocyte mono-immunoglobulin-like receptor 3 (CD300f) can negatively regulate MCs degranulation. Identification of drug candidates which target CD300f represents a promising prospect in drug development. Myricetin is widely distributed in plants and has been reported to inhibit allergic reactions in OVA-induced murine models.
This study aims to determine whether myricetin can activate CD300f to arrest MCs degranulation mediated by MRGPRX2.
Myricetin inhibited the allergic mediator and cytokine release triggered by MRGPRX2 in vivo and in vitro. Under C48/80 stimulation, the release of β-hexosaminidase, TNF-α, IL-8 and MCP-1 in CD300f knockdown in LAD2 cells was significantly increased compared with NC-LAD2 cells. Myricetin displayed good structural affinity (K = 7.21 × 10) with CD300f by SPR. Molecular docking results showed that hydrogen bonds were formed between myricetin and CD300f, indicating high binding ability (5.6653). Myricetin can upregulate the phosphorylation of SHP-1 and SHP-2 and dephosphorylation in the MRGPRX2 signaling pathway, involving PLCγ1, AKT, P38, and ERK1/2.
In the present study, myricetin is identified as an exogenous ligand for CD300f, which negatively regulates MRGPRX2-mediated MCs activation via CD300f to inhibit MCs degranulation and pseudo-allergic reactions.
Mas 相关 G 蛋白偶联受体 X2（MRGPRX2）在肥大细胞（MCs）脱颗粒和伪过敏反应中发挥重要作用。白细胞单免疫球蛋白样受体 3（CD300f）可负调控 MCs 脱颗粒。鉴定靶向 CD300f 的药物候选物代表了药物开发的一个有前途的前景。杨梅素广泛存在于植物中，已被报道可抑制 OVA 诱导的小鼠模型中的过敏反应。
本研究旨在确定杨梅素是否可以激活 CD300f 来阻止 MRGPRX2 介导的 MCs 脱颗粒。
杨梅素抑制了体内和体外 MRGPRX2 触发的过敏介质和细胞因子释放。在 C48/80 刺激下，与 NC-LAD2 细胞相比，CD300f 敲低的 LAD2 细胞中β-己糖胺酶、TNF-α、IL-8 和 MCP-1 的释放明显增加。SPR 显示杨梅素与 CD300f 具有良好的结构亲和力（K=7.21×10）。分子对接结果表明，杨梅素与 CD300f 形成氢键，表明结合能力高（5.6653）。杨梅素可以上调 MRGPRX2 信号通路中 SHP-1 和 SHP-2 的磷酸化和去磷酸化，涉及 PLCγ1、AKT、P38 和 ERK1/2。
在本研究中，杨梅素被鉴定为 CD300f 的外源性配体，通过 CD300f 负调控 MRGPRX2 介导的 MCs 激活，抑制 MCs 脱颗粒和伪过敏反应。
