IL-10 producing neutrophils during respiratory virus infection

描述（由申请人提供）：呼吸道感染病毒，如流感或呼吸道合胞病毒，是对人类健康的持续挑战，特别是对儿童、老年人和免疫功能低下者。为了控制和清除感染而产生的炎症反应的解除，导致危及生命的呼吸道生理破坏和粘膜屏障完整性的丧失，从而在很大程度上导致了与这些感染相关的高发病率。了解调节感染炎症反应的机制对于确定治疗干预的目标至关重要。我们的数据表明，在呼吸道病毒感染早期招募到肺部的中性粒细胞在调节炎症反应的程度方面起着至关重要的作用。有趣的是，这些中性粒细胞中的一部分产生调节性细胞因子IL-10，这些细胞的IL-10表达受到感染期间肺部产生的抗病毒细胞因子I型干扰素的刺激。由于中性粒细胞在病毒感染的早期阶段被大量招募到肺部，我们假设，在抗病毒炎症环境的反应中，中性粒细胞群体获得了一种调节性表型，这一表型对保护肺部免受损伤和相关病理有重要作用。支持这一假设的是，携带IL-10缺失骨髓细胞的小鼠出现了更严重的肺部炎症，并显示出更高的发病率。在这里，我们将使用尖端技术来表征感染呼吸道合胞病毒（Aim 1）的小鼠肺中产生IL-10的中性粒细胞，我们将确定I型IFN是否需要中性粒细胞保护活性（Aim 2），我们将测试中性粒细胞产生的IL-10是否调节病毒感染的炎症反应（Aim 3）。总的来说，这项探索性R21资助旨在形态学和表型上表征呼吸道病毒感染期间肺中产生il -10的中性粒细胞，并促进我们对其肺保护功能的理解。这些研究将为今后确定中性粒细胞保护活性的分子靶点提供指导。

DESCRIPTION (provided by applicant): Infections of the respiratory tract with viruses such as influenza or respiratory syncytial virus are a constant challenge to human health, particularly to children, the elderly, and the immunocompromised. Deregulation of the inflammatory response developed to control and clear the infection leads to life threatening disruption of the respirator tract physiology and loss of integrity of the mucosal barrier, thereby largely contributing to the high degree of morbidity associated with these infections. Understanding the mechanisms that regulate the inflammatory response to infection is essential to identify targets for therapeutic intervention. Our data indicate that neutrophils that are recruited to the lung early upon respiratory viral infections play an essential role in regulating the extent of the inflammatory response. Interestingly, a fraction of these neutrophils produce the regulatory cytokine IL-10, and IL-10 expression by these cells is stimulated by the antiviral cytokines type I interferons produced in the lung during infection. As neutrophils are massively recruited to the lung at the early stages of viral infections, we hypothesize that in response to the antiviral inflammatory environment, a population of neutrophils acquire a regulatory phenotype that significantly contributes to protection from lung damage and associated pathologies. Supporting this hypothesis, mice bearing IL-10 deficient myeloid cells developed a more severe lung inflammation and showed enhanced morbidity. Here, we will use cutting edge technology to characterize IL-10-producing neutrophils present in the lung of mice infected with respiratory syncytial virus (Aim 1), we will determine whether type I IFN priming is required for the neutrophil protective activity (Aim 2), and we will test whether neutrophil-produced IL-10 modulates the inflammatory response to virus infection (Aim 3). Overall, this exploratory R21 grant aims at morphologically and phenotypically characterizing pulmonary IL-10-producing neutrophils present during respiratory viral infections, and to advance our understanding of their function in lung protection. These studies should guide future identification of molecular targets for the harnessing of the neutrophil protective activities in patients.