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：
10708997
负责人：
Hirohito Kita
金额：
$ 63.59万
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/10708997
关键词：
Adjuvant Affect Air Pollution Airway Disease Allergens Allergic Aluminum Animal Model Apoptosis Asthma Atmosphere CASP3 gene CD4 Positive T Lymphocytes Calpain Cell physiology Cells Cellular Stress Cellular biology Chromosomes Collaborations DNA DNA receptor Development Disease Disease model Environmental Risk Factor Epithelial Cells Epithelium 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 Biology Mucous Membrane Mus Necrosis Nuclear Organ Pathogenesis Pattern Pattern recognition receptor Peptide Initiation Factors Play Prevention strategy Principal Investigator Process Role Sterility TSLP gene Testing Tissues Untranslated Regions Virus Diseases airborne allergen airway epithelium allergic airway disease allergic airway inflammation 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 pharmacologic 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.

项目摘要/摘要该项目的长期目的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理，包括病毒感染，过敏原和空气污染。这是越来越清楚的是，气道上皮在策划免疫反应中起着关键作用呼吸道。尽管如此，对免疫反应的主动性和发展涉及的机制环境因素尚未完全理解。在各种器官的无菌感染中暗示了通过免疫球传感的自发DNA 疾病的病理生理。最近，我们发现人气道上皮细胞迅速释放在体外过敏原暴露后，核DNA进入细胞外环境。 caspase-3迅速激活在过敏原暴露时气道上皮细胞中，没有明显的细胞凋亡或坏死迹象。自己- DNA也被释放到暴露于体内过敏原的幼稚小鼠的气道管腔中，并阻塞细胞外DNA（EDNA）抑制了对过敏原的2型免疫回报。因此，我们假设过敏原引起的气道上皮细胞的自动DNA的快速细胞外释放促进2型免疫对机载过敏原的反应。本提案中描述的实验将通过关注两个基本来研究这一假设问题。在AIM 1中，我们将确定气道上皮细胞迅速释放的DNA响应于过敏原暴露于体外。我们将研究caspase-3和 Calpains分别启动和终止主动DNA释放。在AIM 2中，我们将确定如何上皮衍生的EDNA促进了2型免疫疗法和体内过敏性气道注射。我们将研究模式识别受体在高级糖基化最终产物（RAGE）中的作用 EDNA和领先的夸大效应子功能的2组先天淋巴样细胞和CD4+ T细胞的功能。我们将在气道的细胞和分子生物学方面采用互补专业知识的结合 O'Grady博士实验室的2型免疫培养物的上皮细胞以及免疫学和疾病模型和疾病模型 Kita博士分别。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气道上皮如何对环境过敏原的反应和将定义负责气道2型免疫反应的关键分子。最终，这些研究将表征过敏原诱导的免疫反应所涉及的关键机制，从而使鉴定新型热目标用于治疗和理想预防免疫介导的气道疾病，例如哮喘，慢性鼻孔炎和其他过敏性疾病。