Nat Med：嗜中性粒细胞介导胰岛素耐受性产生

嗜中性粒细胞扫描电子显微图。

来自美国加州大学圣地亚哥分校医学院的研究人员说，数量丰富的一类白细胞，即嗜中性粒细胞(neutrophil)，通常起着攻击细菌和其他外来入侵物的作用，然而它们也在调控胰岛素耐受性上也发挥着一种令人意想不到的作用，其中胰岛素耐受性是II型糖尿病的主要特征。2012年8月5日，这些研究发现在线发表在Nature Medicine期刊上。

嗜中性粒细胞是首批对组织炎症作出反应的免疫细胞，能够通过招募巨噬细胞来促进慢性炎症产生。慢性低度炎症(chronic low-grade inflammation)在脂肪组织中比较常见，是一种产生系统性胰岛素耐受性的重要原因。

利用小鼠和人类肝细胞以及活的小鼠模式动物，加州大学圣地亚哥分校医学教授Jerrold M. Olefsky博士领导的一个研究小组发现嗜中性粒细胞分泌出的一种酶，即嗜中性粒细胞弹性蛋白酶(neutrophil elastase, NE)，损害胰岛素信号通路，从而促进胰岛素耐受性产生。相反地，剔喂食高脂肪食物的肥胖小鼠中的NE，能够改善小鼠对胰岛素的敏感性。

特别地，嗜中性粒细胞利用NE来激活一种触发吞噬病原体的巨噬细胞分泌促炎症分子(proinflammatory molecule)的信号通路。NE降解一种在肝细胞和脂肪细胞胰岛素信号通路中发挥关键性作用的蛋白IRS1。尽管已知NE在肺癌细胞中降解这种蛋白，但是它对诸如肝脏和脂肪组织之类的胰岛素靶组织的影响是十分显著的。嗜中性粒细胞调节胰岛素的作用使得它们成为一种新的靶标，从而能够被用来开发出新的治疗方法来治疗胰岛素耐受性和糖尿病。

本文编译自Neutrophils: White blood cells mediate insulin resistance

doi: 10.1038/nm.2885
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Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase

Saswata Talukdar, Da Young Oh, Gautam Bandyopadhyay, Dongmei Li, Jianfeng Xu, Joanne McNelis, Min Lu, Pingping Li, Qingyun Yan, Yimin Zhu, Jachelle Ofrecio, Michael Lin, Martin B Brenner & Jerrold M Olefsky

Chronic low-grade adipose tissue and liver inflammation is a major cause of systemic insulin resistance and is a key component of the low degree of insulin sensitivity that exists in obesity and type 2 diabetes1, 2. Immune cells, such as macrophages, T cells, B cells, mast cells and eosinophils, have all been implicated as having a role in this process3, 4, 5, 6, 7, 8. Neutrophils are typically the first immune cells to respond to inflammation and can exacerbate the chronic inflammatory state by helping to recruit macrophages and by interacting with antigen-presenting cells9, 10, 11. Neutrophils secrete several proteases, one of which is neutrophil elastase, which can promote inflammatory responses in several disease models12. Here we show that treatment of hepatocytes with neutrophil elastase causes cellular insulin resistance and that deletion of neutrophil elastase in high-fat-diet–induced obese (DIO) mice leads to less tissue inflammation that is associated with lower adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity. Taken together, we show that neutrophils can be added to the extensive repertoire of immune cells that participate in inflammation-induced metabolic disease.