Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis.
Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis.
复制标题
DOI：
10.1136/gutjnl-2014-306998
复制
发表时间：
2015-08
期刊：
影响因子：
24.5
通讯作者：
Furuta GT
中科院分区：
文献类型：
--
作者：
Masterson JC;McNamee EN;Fillon SA;Hosford L;Harris R;Fernando SD;Jedlicka P;Iwamoto R;Jacobsen E;Protheroe C;Eltzschig HK;Colgan SP;Arita M;Lee JJ;Furuta GT
嗜酸性粒细胞存在于结肠粘膜中，并在疾病期间显著增加。尽管许多研究表明嗜酸性粒细胞有助于GI炎症的发病机制，但嗜酸性粒细胞介导的活动范围的扩大表明它们也调节局部免疫应答并调节组织炎症。我们试图确定嗜酸性粒细胞对小鼠结肠炎急性期的影响。通过向C57 BL/6 J（对照）或嗜酸性粒细胞缺乏（PHIL）小鼠施用葡聚糖硫酸钠、2，4，6-三硝基苯磺酸或恶唑酮在小鼠中诱导急性结肠炎。还使用抗白细胞介素（IL）-5的抗体或通过将PHIL小鼠的骨髓移植到对照小鼠中来从小鼠中去除嗜酸性粒细胞。收集结肠组织并通过免疫组织化学、流式细胞术和逆转录PCR进行分析;通过质谱分析脂质。与对照组相比，嗜酸性粒细胞缺乏的小鼠发生了更严重的结肠炎，其结肠组织中含有更多的中性粒细胞。这种中性粒细胞的代偿性增加伴随着趋化因子CXCL 1和CXCL 2水平的增加，它们吸引中性粒细胞。来自嗜酸性粒细胞缺陷小鼠的结肠组织的脂质组学分析鉴定了二十二碳六烯酸衍生的抗炎介质10，17-二羟基二十二碳六烯酸（diHDoHE），即保护素D1（PD 1）的缺陷。给予外源性PD 1异构体（10 S，17 S-DiHDoHE）可降低嗜酸性粒细胞缺乏小鼠结肠炎的严重程度。PD 1-异构体还减弱了小鼠结肠中的中性粒细胞浸润，并降低了肿瘤坏死因子-α、IL-1β、IL-6和诱导型NO合酶的水平。最后，体外试验确定了PD 1异构体对中性粒细胞跨上皮迁移的直接抑制作用。嗜酸性粒细胞通过产生抗炎脂质介质对小鼠急性结肠炎具有保护作用。
Eosinophils reside in the colonic mucosa and increase significantly during disease. Although a number of studies have suggested that eosinophils contribute to the pathogenesis of GI inflammation, the expanding scope of eosinophil-mediated activities indicate that they also regulate local immune responses and modulate tissue inflammation. We sought to define the impact of eosinophils that respond to acute phases of colitis in mice. Acute colitis was induced in mice by administration of dextran sulfate sodium, 2,4,6-trinitrobenzenesulfonic acid or oxazolone to C57BL/6J (control) or eosinophil deficient (PHIL) mice. Eosinophils were also depleted from mice using antibodies against interleukin (IL)-5 or by grafting bone marrow from PHIL mice into control mice. Colon tissues were collected and analysed by immunohistochemistry, flow cytometry and reverse transcription PCR; lipids were analysed by mass spectroscopy. Eosinophil-deficient mice developed significantly more severe colitis, and their colon tissues contained a greater number of neutrophils, than controls. This compensatory increase in neutrophils was accompanied by increased levels of the chemokines CXCL1 and CXCL2, which attract neutrophils. Lipidomic analyses of colonic tissue from eosinophil-deficient mice identified a deficiency in the docosahexaenoic acid-derived anti-inflammatory mediator 10, 17- dihydroxydocosahexaenoic acid (diHDoHE), namely protectin D1 (PD1). Administration of an exogenous PD1-isomer (10S, 17S-DiHDoHE) reduced the severity of colitis in eosinophil-deficient mice. The PD1-isomer also attenuated neutrophil infiltration and reduced levels of tumour necrosis factor-α, IL-1β, IL-6 and inducible NO-synthase in colons of mice. Finally, in vitro assays identified a direct inhibitory effect of PD1-isomer on neutrophil transepithelial migration. Eosinophils exert a protective effect in acute mouse colitis, via production of anti-inflammatory lipid mediators.