Mechanisms of IL-33 secretion in allergic diseases

IL-33分泌在过敏性疾病中的机制

• 批准号: 9231814
• 负责人: Hirohito Kita
• 金额: $ 52.27万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-16 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231814
• 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; Epithelium; 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; injured; mouse model; new therapeutic target; novel; overexpression; prevent; receptor; receptor for advanced glycation endproducts; sensor; small molecule; treatment strategy

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.

项目摘要/摘要 在全球范围内，过敏性疾病和哮喘的患病率正在增加。这些疾病经常发生 在同一个人中一起表明存在常见的潜在免疫病因素。 该项目的长期目标是调查涉及的基本免疫机制 过敏性疾病的发展。越来越清楚的是，上皮产生的细胞因子 屏障表面的细胞，包括胸腺基质淋巴细胞增生素，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。但是，主要差距仍然 在我们的知识中，关于生产的分子和细胞控制和分泌的知识 细胞因子。该应用程序的目的是通过关注IL-33来解决这些差距。 IL-33通常存储在非血液学细胞的核中。我们最近发现 人类气道上皮细胞到真菌过敏原，替代品，唤起细胞外释放 触发细胞内钙浓度和IL-33分泌的ATP持续增加 细胞外环境。我们还发现，当ATP释放和IL-33分泌都被废除 ROS清除剂和NRF2的小分子激活剂减少了活性氧（ROS），它们 增加内源性抗氧化剂酶的表达。分泌的IL-33已被处理为19 全长31 kDa形式的KDA形式。因此，我们假设在接触空中时 过敏原，气道上皮的氧化应激反应触发ATP的细胞外释放，导致 高度活性IL-33的蛋白水解处理和分泌。 拟议的研究旨在详细研究此过程的关键步骤。在AIM 1中，我们将 确定氧化应激如何启动并维持ATP从气道上皮细胞中释放，这是一个关键 触发IL-33分泌的步骤。在AIM 2中，我们将调查空气传播过敏原暴露如何诱导 通过研究高级糖基化最终产物的受体的作用，气道上皮中的氧化应激 （愤怒）。在AIM 3中，我们将检查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 互补的分子，细胞生物学，药理和免疫学专业知识 O'Grady博士和Kita博士。为该项目开发了新颖和健壮的体外和体内模型。 这些研究将更好地了解上皮对环境过敏原的反应 并将定义负责IL-33分泌的关键免疫病理生理机制。最终， 这些研究将为过敏原诱导的关键分子提供重要的表征 免疫反应，允许鉴定新的治疗靶标的治疗，理想情况下 免疫介导的疾病，例如哮喘，慢性鼻孔炎和过敏性疾病。