Human Eosinophils: Mechanisms of Functioning

嗜酸性粒细胞在健康以及哮喘、过敏和其他疾病的发病机制中发挥作用。作为单元格 先天免疫系统，嗜酸性粒细胞的一个独特属性是它们的内容中已经合成了多个 细胞因子与颗粒阳离子蛋白一起储存在嗜酸性粒细胞胞质颗粒和小泡内。 确定嗜酸性粒细胞之间的功能相互作用，由其分泌的阳离子和细胞因子介导 蛋白质和组织中的其他细胞与了解嗜酸性粒细胞在两种持续免疫中的功能密切相关 动态平衡和急慢性疾病。组织部位的嗜酸性粒细胞显示超微结构证据 脱粒的两种形式：1)分段脱粒，通过这种脱粒，颗粒内容物被动员到 由细胞质分泌的小泡分泌，以及2)通过细胞溶解挤出的完整颗粒的释放 在嗜酸性粒细胞内。我们建立了无细胞的嗜酸性粒细胞表达配体结合的细胞因子和 二十烷类受体，激活颗粒内信号，刺激颗粒分离。两种激动剂- 在完整的嗜酸性粒细胞和游离颗粒内的分泌物中特定的零星脱颗粒可以 选择性和差异性地释放阳离子蛋白质和体内储存的许多细胞因子 颗粒。研究将探讨嗜酸性粒细胞来源的调节释放的机制 蛋白质，包括细胞因子和阳离子蛋白质。总体的假设是，对于 嗜酸性粒细胞与相关嗜酸性粒细胞蛋白在细胞内的区隔、运输和释放 来自嗜酸性粒细胞和他们的游离颗粒依赖于调节机制，在刺激- 依赖特异性可以很好地调节细胞因子的差异性和选择性分泌。我们的目标将 探讨：1)调节无细胞嗜酸性粒细胞分泌能力的机制；2) 调节嗜酸性粒细胞内分泌细胞因子和其他蛋白质的机制； 依赖刺激的嗜酸性粒细胞细胞因子的动员和定向释放。了解分子和 调节嗜酸性粒细胞衍生蛋白胞外释放的细胞机制将提供 深入了解嗜酸性粒细胞的功能，包括嗜酸性粒细胞与其他细胞之间的相互作用。 相关性(请参阅说明)： 与嗜酸性粒细胞相关的疾病，包括哮喘、过敏和其他疾病，越来越普遍。 疾病和重大公共卫生问题。更好地了解嗜酸性粒细胞在这些疾病中的作用 疾病可能会导致这些疾病的治疗方法得到改进。

Eosinophils function in health and in the pathogeneses of asthma, allergies and other diseases. As cells of the innate immune system, a distinct attribute of eosinophils is their content of multiple already synthesized cytokines stored, along with granule cationic proteins, within eosinophil cytoplasmic granules and vesicles. Defining functional interactions between eosinophils, mediated by their secreted cationic and cytokine proteins, and other cells in tissues is germane to understanding eosinophil functions in both ongoing immune homeostasis and acute and chronic diseases. Eosinophils in tissue sites exhibit ultrastructural evidence of two forms of "degranulation:" 1) piecemeal degranulation by which granule contents are mobilized into and secreted by cytoplasmic secretory vesicles, and 2) release of intact granules extruded by cytolysis from within eosinophils. We established that cell-free eosinophil granules express ligand-binding cytokine and eicosanoid receptors that activate intragranular signaling to stimulate secetion from granules. Both agonist- specific piecemeal degranulation from within intact eosinophils and secretion from within free granules can release, selectively and differentially, cationic proteins and some of the many cytokines stored within granules. Studies will investigate mechanisms involved in the regulated release of eosinophil-derived proteins, including cytokines and cationic proteins. The overall hypothesis is that, central to the functions of eosinophils, the intracellular compartmentalization, trafficking and release of relevant eosinophil proteins from eosinophils and their free granules are dependent on regulatory mechanisms that with stimulus- dependent specificity can finely regulate the differential and selective secretion of cytokines. Our Aims will investigate: 1) mechanisms regulating the secretion competence of cell-free eosinophil granules; 2) mechanisms mediating the secretion of cytokines and other proteins from within eosinophils; and 3) stimulus-dependent mobilization and targeted release of eosinophil cytokines. Understanding molecular and cellular mechanisms that regulate the extracellular release of eosinophil granule-derived proteins will provide insights into eosinophil functions that involve interactions between esosinophils and other cells. RELEVANCE (See instructions): Eosinophil-associated diseases, including asthma, allergies and other disorders, are increasingly prevalent diseases and major public health problems. Better understanding of the functions of eosinophils in these diseases may lead to improved therapies for these diseases.