Yousefi Shida, Gold Jeffrey A, Andina Nicola, Lee James J, Kelly Ann M, Kozlowski Evelyne, Schmid Inès, Straumann Alex, Reichenbach Janine, Gleich Gerald J, Simon Hans-Uwe
Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
Nat Med. 2008 Sep;14(9):949-53. doi: 10.1038/nm.1855.
Although eosinophils are considered useful in defense mechanisms against parasites, their exact function in innate immunity remains unclear. The aim of this study is to better understand the role of eosinophils within the gastrointestinal immune system. We show here that lipopolysaccharide from Gram-negative bacteria activates interleukin-5 (IL-5)- or interferon-gamma-primed eosinophils to release mitochondrial DNA in a reactive oxygen species-dependent manner, but independent of eosinophil death. Notably, the process of DNA release occurs rapidly in a catapult-like manner--in less than one second. In the extracellular space, the mitochondrial DNA and the granule proteins form extracellular structures able to bind and kill bacteria both in vitro and under inflammatory conditions in vivo. Moreover, after cecal ligation and puncture, Il5-transgenic but not wild-type mice show intestinal eosinophil infiltration and extracellular DNA deposition in association with protection against microbial sepsis. These data suggest a previously undescribed mechanism of eosinophil-mediated innate immune responses that might be crucial for maintaining the intestinal barrier function after inflammation-associated epithelial cell damage, preventing the host from uncontrolled invasion of bacteria.
尽管嗜酸性粒细胞被认为在抵抗寄生虫的防御机制中发挥作用，但其在固有免疫中的具体功能仍不清楚。本研究的目的是更好地了解嗜酸性粒细胞在胃肠道免疫系统中的作用。我们在此表明，革兰氏阴性菌的脂多糖以依赖活性氧的方式激活白细胞介素-5（IL-5）或干扰素-γ预处理的嗜酸性粒细胞，使其释放线粒体DNA，但与嗜酸性粒细胞死亡无关。值得注意的是，DNA释放过程以类似弹射的方式迅速发生——不到一秒钟。在细胞外空间，线粒体DNA和颗粒蛋白形成细胞外结构，能够在体外和体内炎症条件下结合并杀死细菌。此外，在盲肠结扎和穿刺后，Il5转基因小鼠而非野生型小鼠表现出肠道嗜酸性粒细胞浸润和细胞外DNA沉积，并伴有对微生物败血症的保护作用。这些数据提示了一种先前未描述的嗜酸性粒细胞介导的固有免疫反应机制，这可能对炎症相关上皮细胞损伤后维持肠道屏障功能、防止宿主受到细菌的无节制入侵至关重要。
