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：
10320382
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320382
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 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 base cytokine early childhood hyperoxia induced lung injury in vivo infancy infant infection inhibitor lung maturation macrophage neonatal mice neonate novel repair function respiratory virus response targeted agent therapeutic target 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.

概括现在已经认识到，感染具有某些呼吸道病毒的普遍易感人群，包括人类鼻病毒（HRV）和呼吸突触病毒（RSV），在婴儿期或幼儿铅期间随后发生过敏性哮喘的风险增加。早产的幸存者，没有和没有支气管肺发育不良（BPD）的并发症，暴露于病毒感染的敏感性增加，并且更大与年龄婴儿相比，患儿童期性哮喘的风险。此外，感染过敏性哮喘的儿童使用这些病毒会严重加剧正在进行的疾病。尽管认识到这种关系，但将病毒感染和敏感性与过敏性肺注射的严重程度联系起来的机制尚不清楚代表关键的未满足需求。我们已经表明，病毒感染诱导巨噬细胞的IL-4RA依赖性，替代激活（MF）在清除病毒后很长的小鼠肺中称为“ M2”（感染后90天）。毛皮- 热线，我们表明过敏原诱导肺中的M2，并且M2积极培养基增强了过敏性内部。燃烧。将IL-4RA的高度纯化的MF转移到IL-4RA - / - 小鼠中导致不同的 - 在肺中诱导病毒诱导的促炎病理学的M2诱导，作为其修复功能的一部分 tion。但是，他们产生了Th2促进细胞因子，并积极促进了过敏原诱导的Th2驱动的Al- 与哮喘有关的Lergic炎症。最近的研究表明，M2 MF极化是相关的随着正常的牙槽发育的发展，并增加了M2极化因高氧诱导的肺内的影响新生儿小鼠的陪审团。根据我们最近的出版物和此应用中描述的其他初步数据阳离子，我们提出了一个新的假设，即增强了对过敏原暴露的反应性年轻小鼠的病毒感染部分是由长寿命M2介导的。我们进一步提出，病毒引起的发病剂 - 正在进行的过敏性疾病的Bation由M2介导。为了检验这一假设，我们将完成以下内容具体目的：1）确定病毒和过敏原暴露之间维持M2的机制； 2）到分析MFS在病毒引起的对过敏原和病毒诱导的EXAC的反应增强的反应中的特定作用灌输； 3）表征M2对新生儿对病毒诱导的敏感性的贡献体内过敏性炎症的造成。该项目将受益于3个PI的专业知识和监督。在这些研究的结论下，我们期望确定病毒感染导致长寿命M2发展的机制增强生命后期哮喘的发展。他们将确定肺M2形成中是否发生变化在肺部成熟期间导致病毒增强哮喘，从而提供了潜在的治疗靶标。