Mechanisms of IL-33 secretion in allergic diseases

IL-33分泌在过敏性疾病中的机制

基本信息

批准号：
10063933
负责人：
Hirohito Kita
金额：
$ 51.65万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063933
关键词：
AKT Signaling Pathway Address Allergens Allergic Allergic Disease Alternaria Animal Model Asthma Biochemistry Biological Pharmacology Calcium Calpain Caspase Cell Death Cell Nucleus Cell physiology Cell secretion Cells Cellular biology Collaborations Connexin 43 Development Disease Drug Hypersensitivity Environmental Exposure Epithelial Epithelial Cells Etiology Event Exposure to Extrinsic asthma Family Functional disorder Genome Human Immune Immune response Immunity Immunologics Immunology In Vitro Individual Interleukin-1 Knowledge Laboratories Length Literature Lung Mediating Modeling Molecular Mucous Membrane NADPH Oxidase Necrosis Nuclear Oxidative Stress Oxidative Stress Induction Pathologic Pathway interactions Patients Peptide Hydrolases Physiology Play Population Prevalence Prevention strategy Principal Investigator Process Production Proteolytic Processing Reactive Oxygen Species Rhinitis Role Severity of illness Shapes Skin Surface TSLP gene Testing Upper digestive tract structure World Health Organization airborne allergen airway epithelium antioxidant enzyme biological adaptation to stress cell injury chronic rhinosinusitis cytokine design environmental allergen exposed human population extracellular genome wide association study human disease in vivo Model mouse model new therapeutic target novel overexpression prevent receptor receptor for advanced glycation endproducts sensor small molecule treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT The prevalence of allergic diseases and asthma is increasing worldwide. These diseases often occur together in the same individual, suggesting the presence of common underlying immunopathogenic factors. The long-term objective of this project is to investigate the fundamental immunological mechanisms involved in the development of allergic diseases. It is becoming increasingly clear that cytokines produced by epithelial cells at the barrier surface, including thymic stromal lymphopoietin, IL-25, and IL-33, play an important role in shaping type 2 immunity and in the pathophysiology of allergic diseases in humans. However, major gaps still remain in our knowledge concerning the molecular and cellular control of production and secretion of these cytokines. The objective of this application is to address these gaps by focusing on IL-33. IL-33 is generally stored in the nucleus of non-hematologic cells. We found recently that exposure of human airway epithelial cells to a fungal allergen, Alternaria alternata, evokes a rapid extracellular release of ATP, which triggers sustained increases in intracellular calcium concentration and IL-33 secretion into the extracellular milieu. We also found that both ATP release and IL-33 secretion are abolished when levels of reactive oxygen species (ROS) are reduced by ROS scavengers and small molecule activators of Nrf2, which increases the expression of endogenous antioxidant enzymes. Secreted IL-33 had been processed to a 19 kDa form from the full-length 31 kDa form. Therefore, we hypothesize that, upon exposure to airborne allergens, the oxidative stress response in airway epithelium triggers extracellular release of ATP, resulting in proteolytic processing and secretion of highly active IL-33. The proposed study is designed to investigate the key steps of this process in detail. In Aim 1, we will determine how oxidative stress initiates and sustains the release of ATP from airway epithelial cells, a critical step that triggers IL-33 secretion. In Aim 2, we will investigate how airborne allergen exposure induces oxidative stress in airway epithelium by studying roles for the receptor for advanced glycation endproducts (RAGE). In Aim 3, we will examine the cellular mechanisms involved in the processing and secretion of IL-33 by studying the roles for the epithelium's endogenous protease. We will employ a combination of complementary molecular, cell biological, pharmacological and immunological expertise in the laboratories of Dr. O'Grady and Dr. Kita. Novel and robust in vitro and in vivo models have been developed for this project. These studies will provide a better understanding of how the epithelium responds to environmental allergens and will define the key immunopathophysiologic mechanisms responsible for secretion of IL-33. Ultimately, these studies will provide an important characterization of key molecule(s) involved in allergen-induced immune responses, allowing for identification of novel therapeutic target(s) to treat and ideally to prevent immune-mediated diseases, such as asthma, chronic rhinosinusitis, and allergic disorders.

项目概要/摘要过敏性疾病和哮喘的患病率在全世界范围内不断增加。这些疾病经常发生在同一个体中同时出现，表明存在共同的潜在免疫致病因素。该项目的长期目标是研究涉及的基本免疫学机制过敏性疾病的发展。越来越清楚的是，上皮细胞产生的细胞因子屏障表面的细胞，包括胸腺基质淋巴细胞生成素、IL-25 和 IL-33，在塑造 2 型免疫力和人类过敏性疾病的病理生理学。但仍存在重大差距仍然存在于我们对这些物质的产生和分泌的分子和细胞控制的知识中。细胞因子。本申请的目的是通过关注 IL-33 来弥补这些差距。 IL-33 通常储存在非血液细胞的细胞核中。近期我们发现，曝光的人类气道上皮细胞对真菌过敏原链格孢 (Alternaria alternata) 的反应会引起细胞外快速释放 ATP，触发细胞内钙离子浓度和 IL-33 分泌到细胞内的持续增加细胞外环境。我们还发现，当 ATP 释放和 IL-33 分泌水平降低时，ATP 释放和 IL-33 分泌都会消失活性氧 (ROS) 被 ROS 清除剂和 Nrf2 小分子激活剂减少，增加内源性抗氧化酶的表达。分泌的 IL-33 已被加工成 19 来自全长 31 kDa 形式的 kDa 形式。因此，我们假设，当暴露于空气中时过敏原时，气道上皮的氧化应激反应会触发细胞外 ATP 的释放，从而导致高活性 IL-33 的蛋白水解加工和分泌。拟议的研究旨在详细研究该过程的关键步骤。在目标 1 中，我们将确定氧化应激如何启动和维持气道上皮细胞 ATP 的释放，这是一个关键的触发 IL-33 分泌的步骤。在目标 2 中，我们将研究空气中的过敏原暴露如何诱发通过研究晚期糖基化终产物受体的作用来研究气道上皮的氧化应激（愤怒）。在目标 3 中，我们将研究 IL-33 加工和分泌所涉及的细胞机制通过研究上皮内源性蛋白酶的作用。我们将采用组合实验室中互补的分子、细胞生物学、药理学和免疫学专业知识奥格雷迪博士和基塔博士。该项目已开发出新颖且强大的体外和体内模型。这些研究将有助于更好地了解上皮细胞如何响应环境过敏原并将确定负责 IL-33 分泌的关键免疫病理生理机制。最终，这些研究将提供参与过敏原诱导的关键分子的重要特征免疫反应，允许识别新的治疗靶点来治疗并理想地预防免疫介导的疾病，例如哮喘、慢性鼻窦炎和过敏性疾病。