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Allergen-induced extracellular DNA in type 2 immunity

2 型免疫中过敏原诱导的细胞外 DNA

基本信息

批准号：
10580884
负责人：
Hirohito Kita
金额：
$ 64.91万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580884
关键词：
Affect Air Air Pollution Airway Disease Allergens Allergic Aluminum Animal Model Apoptosis Asthma CASP3 gene CD4 Positive T Lymphocytes Calpain Cell physiology Cells Cellular biology Chromosomes Collaborations DNA DNA receptor Development Disease Disease model Environmental Risk Factor Epithelial Epithelial Cells Etiology Exons Exposure to Functional disorder Heat shock proteins Human Immune Immune response Immunity Immunologics Immunology In Vitro Inflammation Inflammatory Inhalation Knowledge Laboratories Link Lung Lymphoid Cell Mediating Modeling Molecular Molecular Immunology Molecular and Cellular Biology Mucous Membrane Mus Necrosis Nuclear Organ Pathogenesis Pattern Pattern recognition receptor Pharmacology Play Prevention strategy Principal Investigator Process Role Sterility Stress TSLP gene Testing Tissues Untranslated Regions Virus Diseases airborne allergen airway epithelium allergic airway disease allergic airway inflammation base bronchial epithelium chronic rhinosinusitis cytokine ds-DNA environmental allergen experimental study extracellular immunopathology in vivo in vivo Model inflammatory milieu injured insight new therapeutic target novel pathogen prevent promoter receptor for advanced glycation endproducts response treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT The long-term objective of this project is to investigate the fundamental immunological mechanisms involved in the development of asthma and allergic airway diseases. Various atmospheric factors contribute to the pathogenesis of these diseases, including viral infection, allergen exposure, and air pollution. It is becoming increasingly clear that the airway epithelium plays a key role in orchestrating immune responses in the airways. Nonetheless, the mechanisms involved in the initiation and development of immune responses to environmental factors are not fully understood. Sensing of self-DNA by immune cells has been implicated in sterile inflammation in various organs and the pathophysiology of diseases. We recently found that human airway epithelial cells rapidly release fragments of nuclear DNA into the extracellular milieu following allergen exposure in vitro. Caspase-3 was rapidly activated in airway epithelial cells upon allergen exposure without apparent signs of cellular apoptosis or necrosis. Self- DNA was also released into the airway lumen in naïve mice exposed to allergens in vivo, and blocking extracellular DNA (eDNA) suppressed type 2 immune responses to the allergens. Therefore, we hypothesize that allergen-induced rapid extracellular release of self-DNA by airway epithelial cells promotes type 2 immune responses to airborne allergens. The experiments described in this proposal will investigate this hypothesis by focusing on two fundamental questions. In Aim 1, we will determine how DNA is rapidly released by airway epithelial cells in response to allergen exposure in vitro. We will examine the mechanisms of non-canonical activation of caspase-3 and calpains, which initiate and terminate active DNA release, respectively. In Aim 2, we will determine how epithelium-derived eDNA promotes type 2 immunity and allergic airway inflammation in vivo. We will investigate the role of the pattern recognition receptor for advanced glycation endproducts (RAGE) in sensing eDNA and leading exaggerated effector functions of group 2 innate lymphoid cells and CD4+ T cells. We will employ a combination of complementary expertise in cellular and molecular biology of airway epithelial cells and immunology and disease models of type 2 immunity in the laboratories of Dr. O’Grady and Dr. Kita, respectively. Novel and robust in vitro and in vivo models have been developed for this project. These studies will provide a better understanding of how airway epithelium responds to environmental allergens and will define the key molecules responsible for type 2 immune responses in the airways. Ultimately, these studies will characterize the critical mechanism(s) involved in allergen-induced immune responses, allowing for the identification of novel therapeutic target(s) for treating and ideally preventing immune-mediated airway diseases, such as asthma, chronic rhinosinusitis, and other allergic disorders.

项目总结/摘要该项目的长期目标是研究基本的免疫机制参与哮喘和过敏性气道疾病的发展。各种大气因素有助于这些疾病的发病机制，包括病毒感染、过敏原暴露和空气污染。是越来越清楚的是，气道上皮细胞在协调免疫反应中起着关键作用，呼吸道尽管如此，参与免疫反应的启动和发展的机制，环境因素尚未完全了解。免疫细胞对自身DNA的感知与各种器官的无菌炎症有关，并且疾病的病理生理学我们最近发现人类气道上皮细胞快速释放在体外变应原暴露后，核DNA进入细胞外环境。Caspase-3被迅速激活在气道上皮细胞中没有明显的细胞凋亡或坏死迹象。自我- 在体内暴露于过敏原的未处理小鼠中，DNA也被释放到气道腔中，并阻断了细胞外DNA（eDNA）抑制对变应原的2型免疫应答。因此，我们假设过敏原诱导的气道上皮细胞自身DNA的快速细胞外释放促进2型免疫对空气中过敏原的反应本提案中描述的实验将通过关注两个基本假设来研究这一假设。问题.在目标1中，我们将确定气道上皮细胞如何快速释放DNA以响应体外过敏原暴露。我们将研究caspase-3的非经典激活机制，钙蛋白酶，其分别启动和终止活性DNA释放。在目标2中，我们将确定如何上皮来源的eDNA在体内促进2型免疫和变应性气道炎症。我们将研究晚期糖基化终末产物模式识别受体（pattern recognition receptor for advanced glycation endproducts，CDDP）在感知 eDNA和导致第2组先天淋巴细胞和CD 4 + T细胞的效应子功能增强。我们将结合气道细胞和分子生物学领域的互补专业知识上皮细胞和2型免疫的免疫学和疾病模型在O 'Grady博士的实验室，博士Kita，分别。已经为该项目开发了新颖且稳健的体外和体内模型。这些研究将提供更好的了解气道上皮细胞如何对环境过敏原作出反应，将确定负责呼吸道2型免疫反应的关键分子。最终，这些研究将描述过敏原诱导的免疫反应中涉及的关键机制，用于治疗和理想地预防免疫介导气道的新治疗靶点的鉴定疾病，如哮喘、慢性鼻窦炎和其他过敏性疾病。