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槲皮素通过MyD88/IKK/NF-κB和PI3K/AKT/Rac1/Cdc42信号通路减轻MRGPRX2介导的肥大细胞脱颗粒。

Quercetin Attenuates MRGPRX2-Mediated Mast Cell Degranulation via the MyD88/IKK/NF-κB and PI3K/AKT/ Rac1/Cdc42 Pathway.

作者信息

Zhao Chenrui, Ding Yuanyuan, Huang Yihan, Wang Chao, Guo Bin, Zhang Tao

机构信息

Department of Anesthesiology, Xi'an Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, People's Republic of China.

College of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.

出版信息

J Inflamm Res. 2024 Oct 7;17:7099-7110. doi: 10.2147/JIR.S480644. eCollection 2024.

DOI:10.2147/JIR.S480644
PMID:39398230
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11468308/
Abstract

BACKGROUND

CMRF35-like molecule-1 (CLM-1) is a receptor of the CD300 family that inhibits MRGPRX2-mediated mast cell degranulation. Understanding the role and mechanism of CLM-1 agonist has significant implications for the treatment of allergic disease. Quercetin is a natural small molecule compound derived from plants and vegetables that has been shown to prevent histamine release by immune cells.

OBJECTIVE

This study aims to examine the inhibitory effects of quercetin on MRGPRX2-mediated mast cell degranulation via CLM-1.

RESULTS

We found that C48/80 stimulation resulted in significantly increased release of β-hexosaminidase, histamine and Ca in CLM-1-knockdown LAD2 cells than in NC-LAD2 cells. Surface plasmon resonance (SPR) and molecular docking analyses revealed high-affinity binding between quercetin and CLM-1 ( = 2.962×10 mol/L) mediated by the formation of hydrogen bonds. In addition, quercetin can selectively bind to CLM-1 on mast cells, leading to SHP-1 phosphorylation and subsequent inhibition of downstream MyD88/IKK/NF-κB signaling. Furthermore, activation of CLM-1 modulated the surface expression of MRGPRX2 by inhibiting F-actin, leading to internalization of the MRGPRX2 receptor via the PI3K/AKT/ Rac1/Cdc42 pathway.

CONCLUSION

Quercetin is a promising treatment for allergic diseases by acting as a CLM-1 agonist that inhibits MRGPRX2-mediated mast cell degranulation.

摘要

背景

CMRF35样分子-1（CLM-1）是CD300家族的一种受体，可抑制MRGPRX2介导的肥大细胞脱颗粒。了解CLM-1激动剂的作用和机制对过敏性疾病的治疗具有重要意义。槲皮素是一种源自植物和蔬菜的天然小分子化合物，已被证明可阻止免疫细胞释放组胺。

目的

本研究旨在探讨槲皮素通过CLM-1对MRGPRX2介导的肥大细胞脱颗粒的抑制作用。

结果

我们发现，与NC-LAD2细胞相比，C48/80刺激导致CLM-1基因敲低的LAD2细胞中β-己糖胺酶、组胺和钙的释放显著增加。表面等离子体共振（SPR）和分子对接分析显示，槲皮素与CLM-1之间通过氢键形成具有高亲和力结合（解离常数=2.962×10⁻⁶mol/L）。此外，槲皮素可选择性地与肥大细胞上的CLM-1结合，导致SHP-1磷酸化，随后抑制下游MyD88/IKK/NF-κB信号通路。此外，CLM-1的激活通过抑制F-肌动蛋白调节MRGPRX2的表面表达，导致MRGPRX2受体通过PI3K/AKT/Rac1/Cdc42途径内化。

结论

槲皮素作为一种CLM-1激动剂，可抑制MRGPRX2介导的肥大细胞脱颗粒，是一种有前景的过敏性疾病治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/b285be70547d/JIR-17-7099-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/9de16019d35d/JIR-17-7099-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/d5aaa0fc5e83/JIR-17-7099-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/4e36717e822d/JIR-17-7099-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/0eecd44ba4d3/JIR-17-7099-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/9faa8a29ba6f/JIR-17-7099-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/b285be70547d/JIR-17-7099-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/9de16019d35d/JIR-17-7099-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/d5aaa0fc5e83/JIR-17-7099-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/4e36717e822d/JIR-17-7099-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/0eecd44ba4d3/JIR-17-7099-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/9faa8a29ba6f/JIR-17-7099-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48d0/11468308/b285be70547d/JIR-17-7099-g0006.jpg

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