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

摘要 组织驻留巨噬细胞是一个多样化的细胞群体，执行专门的功能， 维持组织的稳态和监视我们最近发现了一种新的肺动脉高压亚型， 小鼠和人类的间质巨噬细胞，定位于肺部，并与 支配神经这些神经和气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 研究中，我们发现NAM增殖旺盛，它们的缺失增强了炎症反应。 感染后的反应。然而，我们对2型NAMs的功能知之甚少 免疫反应。我们的总体目标是描述适应市场机制和适合本国的机制的具体贡献 巴西日本圆线虫（Nb）感染后， 对抗蠕虫病为此，我们建议将联合收割机多参数流式细胞术和 利用我们的先进体内模型和scRNA-seq等尖端基因组方法进行成像 和ATAC-seq.本提案的第一个目标是确定适应市场机制和适合本国的机制的具体职能 在用Nb寄生虫感染后，通过使用选择性消耗AM的体内模型，或 NAM或两者。在第二个目标中，我们将研究支持特定功能的机制 NAMs在建立长期抗寄生虫免疫方面的作用。我们还将使用基因组方法， 无偏倚地评价AM和NAM的染色质可及性以及相关转录组， 允许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 并能从根本上改变我们对与之相关的功能和机制的理解， 肺巨噬细胞，并可以扩展到研究其他肺部疾病，如哮喘， 慢性阻塞性肺疾病（COPD）以及当前全球大流行的COVID 19。

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.