Division of Allergy and Inflammation, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
FASEB J. 2012 May;26(5):2084-93. doi: 10.1096/fj.11-200246. Epub 2012 Jan 31.
Rapid secretion of eosinophil-associated RNases (EARs), such as the human eosinophilic cationic protein (ECP), from intracellular granules is central to the role of eosinophils in allergic diseases and host immunity. Our knowledge regarding allergic inflammation has advanced based on mouse experimental models. However, unlike human eosinophils, capacities of mouse eosinophils to secrete granule proteins have been controversial. To study mechanisms of mouse eosinophil secretion and EAR release, we combined an RNase assay of mouse EARs with ultrastructural studies. In vitro, mouse eosinophils stimulated with the chemokine eotaxin-1 (CCL11) secreted enzymatically active EARs (EC(50) 5 nM) by piecemeal degranulation. In vivo, in a mouse model of allergic airway inflammation, increased airway eosinophil infiltration (24-fold) correlated with secretion of active RNases (3-fold). Moreover, we found that eosinophilic inflammation in mice can involve eosinophil cytolysis and release of cell-free granules. Cell-free mouse eosinophil granules expressed functional CCR3 receptors and secreted their granule proteins, including EAR and eosinophil peroxidase in response to CCL11. Collectively, these data demonstrate chemokine-dependent secretion of EARs from both intact mouse eosinophils and their cell-free granules, findings pertinent to understanding the pathogenesis of eosinophil-associated diseases, in which EARs are key factors.
嗜酸性粒细胞相关核糖核酸酶（EARs），如人嗜酸性阳离子蛋白（ECP），从细胞内颗粒中的快速分泌是嗜酸性粒细胞在过敏疾病和宿主免疫中的作用的核心。我们对过敏炎症的认识是基于小鼠实验模型的。然而，与人类嗜酸性粒细胞不同，小鼠嗜酸性粒细胞分泌颗粒蛋白的能力存在争议。为了研究小鼠嗜酸性粒细胞分泌和 EAR 释放的机制，我们将小鼠 EAR 的核糖核酸酶测定与超微结构研究相结合。在体外，用趋化因子 eotaxin-1（CCL11）刺激的小鼠嗜酸性粒细胞通过颗粒部分脱颗粒分泌具有酶活性的 EARs（EC（50）5 nM）。在体内，在过敏气道炎症的小鼠模型中，气道中嗜酸性粒细胞浸润的增加（24 倍）与活性 RNases 的分泌（3 倍）相关。此外，我们发现，小鼠中的嗜酸性粒细胞炎症可涉及嗜酸性粒细胞细胞溶解和无细胞颗粒的释放。无细胞的小鼠嗜酸性粒细胞颗粒表达功能性 CCR3 受体，并响应 CCL11 分泌其颗粒蛋白，包括 EAR 和嗜酸性过氧化物酶。总的来说，这些数据表明，趋化因子依赖性地从完整的小鼠嗜酸性粒细胞及其无细胞颗粒中分泌 EARs，这对于理解嗜酸性粒细胞相关疾病的发病机制是相关的，EARs 是其中的关键因素。
