Novel lung resident interstitial macrophage subset with distinct localization and polarization

摘要 组织内驻留巨噬细胞对病原体清除和动态平衡的重要性开始显现 浮出水面。然而，我们对这些巨噬细胞在粘膜组织中扮演的多方面角色的理解 因为肺仍然不完整。肺是一个非常复杂的器官，有专门的结构 充足的气体交换。肺微环境是独一无二的，具有直接而重要的影响。 对常驻免疫细胞，特别是巨噬细胞群。目前，肺已被公认为 肺泡巨噬细胞(AM)和间质巨噬细胞是两种不同的巨噬细胞 巨噬细胞(IMS)。肺巨噬细胞最重要的功能之一就是调节炎症 在感染过程中的途径，并允许在病原体清除后消退炎症。精准的 巨噬细胞群体在体内完成这些关键功能的机制还不是很好。 明白了。例如，巨噬细胞在调节病原体诱导的炎症过程中发挥关键作用。 呼吸道感染，如流行性感冒。流感感染导致全球年度流行，导致 数以千计的人死亡和住院。临床并发症是由组织损伤引起的 过度的病毒诱导的免疫反应。因此，迫切需要了解细胞和 体内感染诱导炎症和病理的分子机制以开发新的 减少感染期间破坏性炎症的治疗策略。在这里，我们报告了一个以前的 未特指的肺巨噬细胞亚群，仅位于大细支气管区周围 航空公司。我们将这些细胞称为大气道相关间质巨噬细胞(LAAM)。我们的 初步数据显示，LAAM的转录基因签名在比较时是非常独特的 因此，我们认为这些细胞在AM中起着重要的作用 调节流感引起的体内炎症。此外，LAAM的独特和独家本地化 提示这些巨噬细胞可能在复合体中起着守门人的作用。 肺的结构。因此，我们假设LAAM完全定义了一组新的巨噬细胞 有别于AM等其他肺巨噬细胞，其独特的定位、显著的基因 表达谱，以及对流感感染的显著反应，使它们对调节至关重要 免疫和组织动态平衡以及病原体引起的炎症。我们提出以下目标： 目的：确定LAAM的个体发育、维持和细胞异质性；AIM2：确定 LAAM和AM在感染后的生理意义；目的：为了确定其机制， 允许LAAM在稳定状态或呼吸道感染期间调节免疫/组织动态平衡。

ABSTRACT The importance of tissue resident macrophages for pathogen clearance and homeostasis is beginning to emerge. However, our understanding of the multifaceted roles these macrophages play in mucosal tissues such as the lung remains incomplete. The lung is a very complex organ with specialized structures to allow for adequate gas exchange. The pulmonary microenvironment is unique and has a direct and important influence on the resident immune cells, especially macrophage populations. Currently, it is well established that lung harbors two distinct populations of macrophages known as alveolar macrophages (AMs) and interstitial macrophages (IMs). One of the most important function of pulmonary macrophages is to regulate inflammatory pathways during infection and allow for the resolution inflammation after the pathogen is cleared. The precise mechanisms that macrophage populations utilize to accomplish these critical functions in vivo are not well understood. For example, Macrophages play a critical role in regulating pathogen induced inflammation during a respiratory infection such as with influenza. Influenza infection causes worldwide yearly epidemics resulting in thousands of deaths and hospitalizations. Clinical complications are caused by tissue damage due to excessive viral-induced immune responses. Thus, there is a critical need to understand the cellular and molecular mechanisms that cause infection-induced inflammation and pathology in vivo in order to develop new therapeutic strategies to alleviate damaging inflammation during infection. Here we report a previously uncharacterized subset of pulmonary macrophages that are exclusively localized around the large bronchiole airways. We have termed these cells as large airway associated interstitial macrophages (LAAMs). Our preliminary data show that the transcriptional gene signature of the LAAMs is remarkably unique when compared to AMs with high expression of regulatory genes and thus, we believe that these cells play an important role in regulating influenza-induced inflammation in vivo. Furthermore, the unique and exclusive localization of LAAMs to the large airways suggests that these macrophages may serve a ‘gatekeeper’ function within the complex structure of the lung. Thus, we hypothesize that LAAMs define a novel population of macrophages completely distinct from other pulmonary macrophages such as AMs, and their unique positioning, remarkable gene expression profile, and the notable reaction to influenza infection make them critically important for regulating immune and tissue homeostasis and pathogen-induced inflammation. We propose the following aims: Aim1: To determine the ontogeny, maintenance and cellular heterogeneity of LAAMs; Aim2: To determine the physiological significance of LAAMs and AMs following infection; Aim3: To determine the mechanisms, that allow LAAMs to regulate immune/tissue homeostasis in steady-state conditions or during respiratory infection.