IL-4-activated macrophages: Contribution to allergic lung inflammation linked to viral infection

IL-4 激活的巨噬细胞：导致与病毒感染相关的过敏性肺部炎症

基本信息

批准号：
10532357
负责人：
Achsah D. Keegan
金额：
$ 61.06万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-03 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532357
关键词：
Adoptive Transfer Adult Allergens Allergic Allergic Disease Allergic inflammation Alveolar Asthma Blocking Antibodies Bronchopulmonary Dysplasia CD4 Positive T Lymphocytes CSF1R gene Cells Child Childhood Chromatin Complication Data Development Diphtheria Toxin Disease Exhibits Exposure to Extrinsic asthma Gene Chips Histones House Dust Mite Allergens Human Hyperoxia ITGAM gene ITGAX gene Individual Infant Infection Inflammation Inflammatory Inhalation Interferon-beta Interleukin-4 Knockout Mice Knowledge Lead Life Link Lung Lymphocyte Lymphoid Macrophage Macrophage Activation Macrophage Colony-Stimulating Factor Maintenance Measures Mediating Memory Modeling Mus Mutant Strains Mice Pathology Persons Phenotype Predisposition Premature Birth Process Publications Pulmonary Inflammation Pyroglyphidae Receptor Signaling Reporting Research Project Grants Respiratory Syncytial Virus Infections Respiratory syncytial virus Rhinovirus Risk Role Severities Signal Pathway Survivors Symptoms TLR4 gene Testing Therapeutic Virus Virus Diseases allergic response asthma prevention asthmatic cytokine early childhood hyperoxia induced lung injury in vivo infancy infant infection inhibitor lung maturation neonatal mice neonate novel permissiveness repair function respiratory virus response targeted agent therapeutic target treatment optimization treatment strategy

项目摘要

SUMMARY It is now recognized that infection of genetically susceptible individuals with certain respiratory viruses, including human rhinovirus (HRV) and respiratory syncytial virus (RSV), during infancy or early childhood leads to an increased risk of subsequent development of allergic asthma. Survivors of preterm birth, with and without the complication bronchopulmonary dysplasia (BPD), exhibit increased susceptibility to viral infection and greater risk of developing childhood-onset asthma than term infants. In addition, infection of children with allergic asthma with these viruses can severely exacerbate ongoing disease. Despite the recognition of this relationship, the mechanism linking viral infection and susceptibility to and severity of allergic lung inflammation is not known representing a critical unmet need. We have shown that viral infection induces the IL-4Ra-dependent, alternative activation of macrophages (Mf) referred to as “M2” in lungs of mice that remain long after virus is cleared (~90 days after infection). Fur- thermore, we showed that allergens induce M2 in the lung and that M2 actively mediate enhanced allergic in- flammation. Adoptive transfer of highly purified Mf that express IL-4Ra into IL-4Ra-/- mice resulted in the differ- entiation of M2 in the lung that mitigated virus-induced pro-inflammatory pathology, as part of their repair func- tion. However, they produced Th2-promoting cytokines and actively promoted allergen-induced, Th2-driven al- lergic inflammation associated with asthma. Recent studies demonstrated that M2 Mf polarization is associated with normal alveolar development, and increased M2 polarization protected against hyperoxia-induced lung in- jury in neonatal mice. Based on our recent publications and additional preliminary data described in this appli- cation, we propose the novel hypothesis that enhanced responsiveness to allergen exposure that occurs after viral infection of young mice is in part mediated by long-lived M2. We further propose that virus-induced exacer- bation of ongoing allergic disease is mediated by M2. To test this hypothesis, we will complete the following specific aims: 1) to determine the mechanism for M2 maintenance between virus and allergen exposure; 2) to analyze the specific role of Mfs on the virus-induced enhanced responses to allergen and virus-induced exac- erbation; and 3) to characterize the contribution M2 to enhanced susceptibility of neonates to virus-induced inception of allergic inflammation in vivo. This project will benefit from the expertise and oversight of the 3 PIs. At the conclusion of these studies, we expect to have determined the mechanism by which viral infection leads to development of long-lived M2 that enhance the development of asthma later in life. They will determine whether alterations in lung M2 formation during lung maturation lead to virus-enhanced asthma, thus providing a potential therapeutic target.

概括现在人们认识到，遗传易感个体感染某些呼吸道病毒，包括人类鼻病毒 (HRV) 和呼吸道合胞病毒 (RSV)，在婴儿期或幼儿期导致早产幸存者随后患过敏性哮喘的风险增加。并发症支气管肺发育不良（BPD），表现出对病毒感染的易感性增加，并且罹患儿童期哮喘的风险高于足月婴儿，此外，儿童感染过敏性哮喘的风险也更高。尽管人们认识到这种关系，但这些病毒可能会严重恶化正在发生的疾病。病毒感染与过敏性肺部炎症的易感性和严重程度之间的联系机制尚不清楚代表未满足的关键需求。我们已经证明，病毒感染会诱导巨噬细胞依赖 IL-4Ra 的选择性激活 (Mf) 被称为小鼠肺部的“M2”，在病毒被清除后仍保留很长时间（感染后约 90 天）。此外，我们发现过敏原在肺部诱导 M2，并且 M2 主动介导增强的过敏反应。将表达 IL-4Ra 的高度纯化的 Mf 过继转移至 IL-4Ra-/- 小鼠中导致了不同的结果。 M2 在肺部的作用减轻了病毒诱导的促炎病理，作为其修复功能的一部分然而，它们产生促进 Th2 的细胞因子并促进过敏原诱导的、Th2 驱动的活性。最近的研究表明，M2 Mf 极化与哮喘相关。肺泡发育正常，M2 极化增强可防止高氧诱导的肺损伤基于我们最近的出版物和本申请中描述的其他初步数据。阳离子，我们提出了一个新的假设，即增强对过敏原暴露后发生的反应年轻小鼠的病毒感染部分是由长寿的 M2 介导的。持续性过敏性疾病的缓解是由 M2 介导的。为了检验这一假设，我们将完成以下工作。具体目标： 1) 确定病毒和过敏原暴露之间 M2 维持的机制；分析Mfs对病毒引起的过敏原增强反应和病毒引起的exac-的具体作用 erbation；和 3) 表征 M2 对新生儿病毒诱导的易感性增强的贡献体内过敏性炎症的开始。该项目将受益于 3 位 PI 的专业知识和监督。我们希望能够确定病毒感染导致长寿命 M2 发育的机制他们将确定肺 M2 形成是否发生改变。在肺成熟期间导致病毒增强的哮喘，从而提供了潜在的治疗靶点。