Ganglioside <scp>GM3</scp> deficiency enhances mast cell sensitivity
Ganglioside <scp>GM3</scp> deficiency enhances mast cell sensitivity
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神经节苷脂<scp>GM3</scp>缺乏增强肥大细胞敏感性
DOI：
10.1111/febs.16806
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Yamashit
中科院分区：
文献类型：
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作者：
Komuro Mariko;Mizugaki Hinano;Nagane Masaki;Morimoto Misako;Fukuyama Tomoki;Ogihara Kikumi;Naya Yuko;Yokomori Emi;Kaneshima Kimika;Kawakami Yasushi;Kamiie Junichi;Shibata Yuki;Suzuki Mira;Shimizu Takuto;Kawashima Nagako;Okamoto Mariko;Ikeda Teruo;Yamashit
肥大细胞是细胞因子和趋化因子的重要来源，在病理过程中发挥作用。神经节苷脂是具有糖链的复合脂质，存在于所有真核细胞膜中并构成脂筏。神经节苷脂GM 3是神经节苷脂合成途径中的第一个神经节苷脂，是特定衍生物的常见前体，并且以其在生物系统中的各种功能而众所周知。肥大细胞含有高水平的神经节苷脂;然而，GM 3参与肥大细胞的敏感性尚不清楚。因此，在这项研究中，我们阐明了神经节苷脂GM 3在肥大细胞和皮肤炎症中的作用。GM 3合酶（GM 3S）缺陷型肥大细胞在IgE-DNP刺激后表现出胞质颗粒拓扑结构变化和过度活化，而不影响增殖和分化。此外，GM 3S缺陷型骨髓源性肥大细胞（BMMC）中的炎性细胞因子水平升高。此外，GM 3S-KO小鼠和GM 3S-KO BMMC移植显示皮肤过敏反应增加。除了由GM 3S缺乏引起的肥大细胞超敏反应外，膜完整性降低，而GM 3补充挽救了这种膜完整性的丧失。此外，GM 3S缺陷增加了p38丝裂原活化蛋白激酶的磷酸化。这些结果表明，GM 3增加膜完整性，导致抑制BMMC中的p38信号通路，并有助于皮肤过敏反应。
Mast cells are a significant source of cytokines and chemokines that play a role in pathological processes. Gangliosides, which are complex lipids with a sugar chain, are present in all eukaryotic cell membranes and comprise lipid rafts. Ganglioside GM3, the first ganglioside in the synthetic pathway, is a common precursor of the specifying derivatives and is well known for its various functions in biosystems. Mast cells contain high levels of gangliosides; however, the involvement of GM3 in mast cell sensitivity is unclear. Therefore, in this study, we elucidated the role of ganglioside GM3 in mast cells and skin inflammation. GM3 synthase (GM3S)‐deficient mast cells showed cytosolic granule topological changes and hyperactivation upon IgE‐DNP stimulation without affecting proliferation and differentiation. Additionally, inflammatory cytokine levels increased in GM3S‐deficient bone marrow–derived mast cells (BMMC). Furthermore, GM3S‐KO mice and GM3S‐KO BMMC transplantation showed increased skin allergic reactions. Besides mast cell hypersensitivity caused by GM3S deficiency, membrane integrity decreased and GM3 supplementation rescued this loss of membrane integrity. Additionally, GM3S deficiency increased the phosphorylation of p38 mitogen‐activated protein kinase. These results suggest that GM3 increases membrane integrity, leading to the suppression of the p38 signalling pathway in BMMC and contributing to skin allergic reaction.