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.

项目概要/摘要该项目的长期目标是研究基本的免疫机制各种大气因素都会导致哮喘和过敏性气道疾病的发生。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。越来越清楚的是，气道上皮在协调免疫反应中起着关键作用然而，涉及免疫反应启动和发展的机制。环境因素尚未完全了解。免疫细胞对自身 DNA 的感知与多种器官的无菌炎症有关，并且我们最近发现人类气道上皮细胞快速释放碎片。体外暴露于过敏原后，核 DNA 进入细胞外环境，Caspase-3 被迅速激活。暴露于过敏原后的气道上皮细胞中没有明显的细胞凋亡或坏死迹象。 DNA 也被释放到体内暴露于过敏原的幼鼠的气道腔中，并阻断细胞外 DNA (eDNA) 抑制对过敏原的 2 型免疫反应。过敏原诱导气道上皮细胞快速释放自身 DNA，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原理来研究这一假设在目标 1 中，我们将确定气道上皮细胞如何快速释放 DNA 来响应。我们将研究 caspase-3 和非典型激活的机制。钙蛋白酶，分别启动和终止主动 DNA 释放，在目标 2 中，我们将确定如何进行。上皮来源的 eDNA 在体内促进 2 型免疫和过敏性气道炎症。研究晚期糖基化终末产物模式识别受体 (RAGE) 在传感中的作用 eDNA 和第 2 组先天淋巴细胞和 CD4+ T 细胞的主要夸大效应器功能。我们将结合气道细胞和分子生物学方面的互补专业知识 O’Grady 博士实验室的上皮细胞和免疫学以及 2 型免疫疾病模型 Kita 博士分别为该项目开发了新颖且强大的体外和体内模型。研究将更好地了解气道上皮如何对环境过敏原做出反应，这些研究最终将确定负责气道 2 型免疫反应的关键分子。将描述过敏原诱导的免疫反应中涉及的关键机制，从而允许识别新的治疗靶点，用于治疗和理想地预防免疫介导的气道疾病，如哮喘、慢性鼻窦炎和其他过敏性疾病。