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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：
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.

项目总结/文摘