Lung resident macrophage subsets in regulating tissue immunity - Resubmission - 1

摘要 组织驻留巨噬细胞是一组不同的细胞，它们执行特殊的功能，如 维持组织的动态平衡和监控。我们最近发现了一种新的肺型 小鼠和人的间质巨噬细胞，定位于肺部并与之密切接触 神经性的神经。这些神经和呼吸道相关的间质巨噬细胞(NAM)是 在转录和发育上与肺泡巨噬细胞(AM)不同。在我们的流感中 研究发现，NAM旺盛地增殖，它们的缺失加剧了炎症 感染后的反应。然而，我们对NAMS在2型中的功能知之甚少 免疫反应。我们的总体目标是确定AM和NAM的具体贡献 巴西拟青霉感染后2型免疫的实验模型 对抗蠕虫类疾病。为此，我们建议将多参数流式细胞术与 使用我们优雅的活体模型和尖端基因组方法(如scRNA-seq)进行成像 和ATAC-seq.这项建议的第一个目标是确定航空管理处和国家航空管理处的具体职能。 在感染新城疫寄生虫后，通过使用选择性耗尽AM或 NAMS或两者兼有。在第二个目标中，我们将研究支撑特定功能的机制 在建立长期的抗寄生虫免疫力方面。我们还将使用基因组方法来 公正地评估AM和NAMS的染色质可及性以及相关转录本 考虑到它们的关键和独特的功能。我们提出的研究将开辟新的研究途径 可以从根本上改变我们对相关功能和机制的理解 肺巨噬细胞，并可扩展到研究其他肺部疾病，如哮喘， 慢性阻塞性肺疾病(COPD)以及目前的全球大流行COVID19。

Abstract Tissue-resident macrophages are a diverse population of cells that perform specialized functions such as sustaining tissue homeostasis and surveillance. We recently identified a novel subset of pulmonary interstitial macrophages in mice and humans that localize to the lungs and are in close contacts with the innervating nerves. These nerve and airway associated interstitial macrophages (NAMs) are transcriptionally and developmentally distinct from the alveolar macrophages (AMs). In our influenza studies, we found that NAMs proliferate robustly and their absence augmented the inflammatory response following infection. However, we know little to nothing about the functions of NAMs in type 2 immune responses. Our overall goal is to characterize the specific contributions of AMs and NAMs following infection with Nippostrongylus brasiliensis (Nb), an experimental model for type2 immunity against helminths diseases. To this end, we propose to combine multiparametric flow cytometry and imaging with our elegant in vivo models and cutting-edge genomic approaches such as scRNA-seq and ATAC-seq. The first aim of this proposal will characterize specific functions of both AMs and NAMs following an infection with Nb parasites, by using in vivo models with selective depletion of AMs or NAMs or both. In the second aim, we will investigate the mechanisms that underpin specific functions of NAMs in mounting a long-lived anti-parasitic immunity. We will also use genomic approaches to unbiasedly evaluate the chromatin accessibility of AMs and NAMs and correlating transcriptomes that allow for their critical and distinct functions. Our proposed studies will open new avenues of research and can fundamentally change our understanding of the functions and mechanisms related to pulmonary macrophages and can be extended to study other pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD) as well as the current global pandemic COVID19.