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

摘要 现在人们认识到，感染某些呼吸道病毒的遗传易感个体， 包括人类鼻病毒(HRV)和呼吸道合胞病毒(RSV)，在婴儿期或儿童早期 增加了患过敏性哮喘的风险。早产幸存者，有无早产 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和 发生儿童期哮喘的风险高于足月儿。此外，儿童过敏性哮喘的感染 这些病毒可能会严重加剧正在发生的疾病。尽管这种关系得到了承认，但 病毒感染与变态反应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 代表着一种严重的未得到满足的需求。 我们已经证明，病毒感染诱导依赖于IL-4ra的巨噬细胞的交替激活 (Mf)指在病毒清除后很长时间(感染后约90天)仍保留在小鼠肺内的“M2”。毛皮- 此外，我们还表明，变应原诱导肺内M2，M2积极地介导增强的变态反应。 火化。将表达IL-4Ra的高纯度Mf过继转导至IL-4Ra-/-小鼠体内，可使IL-4Ra-/-小鼠产生不同程度的免疫抑制。 识别肺中的M2减轻病毒诱导的促炎病理，作为其修复功能的一部分。 提顿。然而，它们产生Th2促进的细胞因子，并积极促进过敏原诱导的Th2驱动的al- 哮喘相关的过敏性炎症。最近的研究表明，M2中频偏振与 肺泡发育正常，M2极化增加对高氧诱导的肺损伤有保护作用。 新生小鼠的陪审团。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，即对发生在以下情况下的过敏原暴露的反应增强 幼鼠的病毒感染部分是由长寿的M2介导的。我们进一步提出，病毒诱导的精确度- 正在进行的过敏性疾病的缓解是由M2介导的。为了验证这一假设，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；2) 分析MFS在病毒诱导的过敏原增强反应和病毒诱导的过敏性反应中的特殊作用。 以及3)确定M2对提高新生儿对病毒诱导的易感性的贡献 体内开始出现过敏性炎症。 该项目将受益于3个绩效指标的专门知识和监督。在这些研究结束时， 我们希望已经确定了病毒感染导致长寿M2发生的机制 促进晚年哮喘的发展。他们将确定肺M2形成的变化 在肺成熟过程中会导致病毒增强型哮喘，从而提供潜在的治疗靶点。

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.