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:
  • 金额:
    $ 61.06万
  • 依托单位:
  • 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

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.
总结 现在认识到,遗传易感个体感染某些呼吸道病毒, 包括人鼻病毒(HRV)和呼吸道合胞病毒(RSV),在婴儿期或儿童早期 过敏性哮喘的风险增加。早产幸存者,有和没有 并发症支气管肺发育不良(BPD)表现出对病毒感染易感性增加, 患儿童期哮喘的风险高于足月儿。此外,过敏性哮喘患儿感染 这些病毒会严重加重正在进行的疾病。尽管承认这种关系, 病毒感染与变应性肺炎易感性和严重性之间的联系机制尚不清楚 代表了一个关键的未满足的需求。 我们已经证明,病毒感染诱导巨噬细胞IL-4 Ra依赖性的交替激活, (Mf)称为“M2”,在病毒被清除后(感染后约90天)仍然存在。毛皮- 因此,我们发现,过敏原诱导M2在肺和M2积极介导增强过敏性, 炎症将表达IL-4 Ra的高度纯化的Mf连续转移到IL-4 Ra-/-小鼠中, 在肺中诱导M2,减轻病毒诱导的促炎性病理,作为其修复功能的一部分, 是的。然而,它们产生Th 2-促进细胞因子,并积极促进变应原诱导的、Th 2-驱动的al- 与哮喘相关的过敏性炎症。最近的研究表明,M2 Mf极化与 肺泡发育正常,M2极化增加可防止高氧诱导的肺损伤, 新生小鼠损伤。根据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,我们提出了新的假设,即增强了对过敏原暴露后发生的反应性 幼龄小鼠的病毒感染部分由长寿的M2介导。我们进一步提出,病毒诱导的exacer- 进行性变态反应性疾病的缓解由M2介导。为了验证这个假设,我们将完成以下操作 具体目的:1)确定病毒和过敏原暴露之间M2维持的机制; 2) 分析Mfs在病毒诱导的过敏原增强反应和病毒诱导的exac中的特异性作用, 以及3)表征M2对新生儿对病毒诱导的 体内过敏性炎症的开始。 该项目将受益于3名主要研究者的专业知识和监督。在这些研究结束时, 我们希望能够确定病毒感染导致长寿命M2发育的机制, 增强哮喘在以后生活中的发展。他们将确定肺M2形成的改变是否 在肺成熟过程中,病毒可导致病毒增强型哮喘,因此提供了一个潜在的治疗靶点。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Perspectives and potential approaches for targeting neuropilin 1 in SARS-CoV-2 infection.
Recent advances in understanding the role of IL-4 signaling.
  • DOI:
    10.12703/r/10-71
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Keegan AD;Leonard WJ;Zhu J
  • 通讯作者:
    Zhu J
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Achsah D. Keegan其他文献

Achsah D. Keegan的其他文献

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{{ truncateString('Achsah D. Keegan', 18)}}的其他基金

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
  • 批准号:
    10320382
  • 财政年份:
    2019
  • 资助金额:
    $ 61.06万
  • 项目类别:
Role of Semaphorin 4A in Allergic Inflammation
Semaphorin 4A 在过敏性炎症中的作用
  • 批准号:
    9973137
  • 财政年份:
    2018
  • 资助金额:
    $ 61.06万
  • 项目类别:
Role of Semaphorin 4A in Allergic Inflammation
Semaphorin 4A 在过敏性炎症中的作用
  • 批准号:
    10455489
  • 财政年份:
    2018
  • 资助金额:
    $ 61.06万
  • 项目类别:
Role of Semaphorin 4A in Allergic Inflammation
Semaphorin 4A 在过敏性炎症中的作用
  • 批准号:
    10212219
  • 财政年份:
    2018
  • 资助金额:
    $ 61.06万
  • 项目类别:
Role of Semaphorin 4A in Allergic Inflammation
Semaphorin 4A 在过敏性炎症中的作用
  • 批准号:
    9753901
  • 财政年份:
    2018
  • 资助金额:
    $ 61.06万
  • 项目类别:
Insulin Receptor Substrate Signaling in Pulmonary Hypertension
肺动脉高压中的胰岛素受体底物信号转导
  • 批准号:
    10305606
  • 财政年份:
    2017
  • 资助金额:
    $ 61.06万
  • 项目类别:
Insulin Receptor Substrate Signaling in Pulmonary Hypertension
肺动脉高压中的胰岛素受体底物信号转导
  • 批准号:
    10089467
  • 财政年份:
    2017
  • 资助金额:
    $ 61.06万
  • 项目类别:
Regulation of Macrophage Activation by House Dust Mite
屋尘螨对巨噬细胞激活的调节
  • 批准号:
    8541976
  • 财政年份:
    2013
  • 资助金额:
    $ 61.06万
  • 项目类别:
Regulation of Macrophage Activation by House Dust Mite
屋尘螨对巨噬细胞激活的调节
  • 批准号:
    8670552
  • 财政年份:
    2013
  • 资助金额:
    $ 61.06万
  • 项目类别:
Regulation of Macrophage Activation by House Dust Mite
屋尘螨对巨噬细胞激活的调节
  • 批准号:
    9898273
  • 财政年份:
    2013
  • 资助金额:
    $ 61.06万
  • 项目类别:

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