Monocyte-derived alveolar macrophage drives inflammatory response to lung ozone exposure

摘要： 与臭氧（O3）暴露相关的发病率和死亡率是一个重大的公共卫生问题。不像 其他环境暴露，O3相关的发病率和死亡率，在很大程度上与呼吸道疾病有关， 与先前存在的呼吸系统疾病有关。然而，这种现象背后的具体机制 我们对此知之甚少。了解先前的肺损伤如何驱动对后续O3暴露的易感性， 在病毒性肺损伤，如季节性流感病毒引起的肺炎的情况下， 或SARS-CoV-2，持续的COVID-19大流行的病原体。我们的总体假设是 由不同的肺泡巨噬细胞（AMH）亚群驱动。在过去的十年里，几个小组的工作， 包括我们在内的研究表明，长寿、自我维持、组织驻留的AMP 19是占主导地位的 正常小鼠和人肺中免疫细胞类型。组织驻留AMR 2对肺内稳态至关重要， 对病原体和环境暴露的直接反应，包括O3。我们此前曾报道， 鼠O3暴露扩大了组织驻留AMR 2，它们的损失加剧了O3诱导的肺损伤。 相反，在肺损伤（例如病毒感染）期间招募的单核细胞来源的AMR 2增加炎症。我们 先前的研究表明，肺损伤后招募的单核细胞源性AMR 4通过自分泌途径在肺中持续存在， M-CSF/M-CSF受体（M-CSF-R），维持活化表型，并驱动慢性肺部疾病。 将其扩展到人类，我们证明了单核细胞源性AMPDs的丰度和激活状态 与早期肺纤维化患者的肺功能呈负相关。累积起来，我们的 已发表的和初步的数据支持，不同的AMR 2亚群指导正在进行的 炎症及其消退，并提示AMR 4组合物，特别是基线存在， 暴露前激活单核细胞源性AMR 2可增强O3诱导的肺损伤的严重性和持续性。 损伤这一基线状况对于呼吸道病毒感染，包括流感和 SARS-CoV 2诱导单核细胞来源的AMPDs的募集。利用机械小鼠模型，状态- 最先进的谱系追踪系统、单细胞基因组学和受控人体O3暴露的连续采样， 我们将检验这样的假设，即单核细胞衍生的AMRs的丰度和活化状态驱动O3- 通过自分泌M-CSF/M-CSF-R信号转导诱导肺部炎症反应。我们的具体目标是：目标 1：确定自分泌单核细胞来源的肺泡巨噬细胞M-CSF/M-CSF-R信号转导在 维持O3暴露小鼠模型的肺部炎症。目标2：确定是否存在丰度 单核细胞源性AMR 2的活化状态可预测肺生理和炎症反应， 在正常人受试者和既往感染SARS-CoV 2的个体中控制急性O3暴露。 这些结果将支持一种具有重要公共卫生影响的新型转化范式，并确定 一种新的治疗策略，以扭转不利的公众健康影响的O3暴露。

Abstract: Morbidity and mortality associated with ozone (O3) exposures are a substantial public health concern. Unlike other environmental exposures, O3-related morbidity and mortality, is largely linked to respiratory causes and associated with pre-existing respiratory conditions. However, specific mechanisms underlying this phenomenon are poorly understood. Understanding how prior lung injury drives susceptibility to subsequent O3 exposure is particularly important in the context on viral lung injury, such as pneumonia caused by seasonal influenza virus or SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic. Our overall hypothesis is that this is driven by distinct alveolar macrophage (AMØ) subsets. During the past decade, work from several groups, including ours, has demonstrated that long-living, self-maintaining, tissue-resident AMØ are the dominant immune cell type in normal mouse and human lung. Tissue-resident AMØ are essential to lung homeostasis and direct responses to pathogens and environmental exposures, including O3. We have previously reported that murine O3 exposure expands tissue-resident AMØ, and their loss exacerbates O3-induced lung injury. Conversely, monocyte-derived AMØ, recruited during lung injury (e.g. viral infection), augment inflammation. Our group previously showed that monocyte-derived AMØ recruited after lung injury persist in the lung via autocrine M-CSF/M-CSF receptor (M-CSF-R), maintain an activated phenotype, and drive chronic lung diseases. Extending this to humans, we demonstrate that the abundance and activation state of monocyte-derived AMØs negatively correlate with pulmonary function in patients with early pulmonary fibrosis. Cumulatively, our published and preliminary data support that distinct AMØ subsets direct the balance between ongoing inflammation and its resolution and suggest that AMØ composition, particularly the baseline presence and activation of monocyte-derived AMØ, prior to exposure can enhance severity and persistence of O3-induced lung injury. This baseline condition is particularly important as respiratory viral infections, including influenza and SARS-CoV2, induce the recruitment of monocyte-derived AMØs. Leveraging mechanistic mouse models, state- of-the-art lineage-tracing systems, single-cell genomics, and serial sampling in controlled human O3 exposures, we will test the hypothesis that the abundance and activation state of monocyte-derived AMØs drive O3- induced lung inflammatory responses via autocrine M-CSF/M-CSF-R signaling. Our specific aims are: Aim 1: To determine the role of autocrine monocyte-derived alveolar macrophage M-CSF/M-CSF-R signaling in maintaining lung inflammation in mouse models of O3-exposure. Aim 2: To determine whether the abundance and activation status of monocyte-derived AMØ predicts lung physiological and inflammatory responses in controlled acute O3 exposures in normal human subjects and in individuals with prior SARS-CoV2 infection. These results would support a novel translational paradigm with important public health implications, and identify a novel therapeutic strategy to revert the adverse public health effects of O3 exposure.