Omega-3 fatty acid epoxides are autocrine mediators that control the magnitude of IgE-mediated mast cell activation
Omega-3 fatty acid epoxides are autocrine mediators that control the magnitude of IgE-mediated mast cell activation
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DOI：
10.1038/nm.4417
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发表时间：
2017-10
期刊：
影响因子：
82.9
通讯作者：
Y. Shimanaka;N. Kono;Y. Taketomi;M. Arita;Y. Okayama;Yuki Tanaka;Y. Nishito;Tatsuki Mochizuki;H. Kusuhara;A. Adibekian;B. Cravatt;M. Murakami;H. Arai
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文献类型：
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作者：
Y. Shimanaka;N. Kono;Y. Taketomi;M. Arita;Y. Okayama;Yuki Tanaka;Y. Nishito;Tatsuki Mochizuki;H. Kusuhara;A. Adibekian;B. Cravatt;M. Murakami;H. Arai
肥大细胞在包括变态反应的免疫应答中的功能的关键是它们产生脂质介质，其中仅ω-6（ω-6）花生四烯酸衍生的类花生酸已被充分表征。在这里，通过采用全面的脂质组学，我们确定ω-3脂肪酸环氧化物作为新的肥大细胞衍生的脂质介质，并表明它们是由PAF-AH 2，一种氧化磷脂选择性磷脂酶A2产生的。PAF-AH 2的遗传或药理学缺失降低了ω-3环氧化物的稳态产生，导致Fc ε RI交联后肥大细胞活化和过敏反应减弱。从机制上讲，ω-3环氧化物通过下调Srcin 1（一种Src抑制蛋白，通过涉及PPARg的途径抵消Fc γ RI信号传导）促进IgE介导的肥大细胞活化。因此，PAF-AH 2-ω-3 epoxide-Srcin 1轴为变应性疾病提供了新的潜在药物靶点。
Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (ω-6) arachidonate–derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (ω-3) fatty acid epoxides as new mast cell–derived lipid mediators and show that they are produced by PAF-AH2, an oxidized-phospholipid-selective phospholipase A2. Genetic or pharmacological deletion of PAF-AH2 reduced the steady-state production of ω-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following FcɛRI cross-linking. Mechanistically, the ω-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts FcɛRI signaling, through a pathway involving PPARg. Thus, the PAF-AH2–ω-3 epoxide–Srcin1 axis presents new potential drug targets for allergic diseases.