Novel lung resident interstitial macrophage subset with distinct localization and polarization

摘要 组织驻留巨噬细胞对于病原体清除和体内平衡的重要性开始被认识到。 出现。然而，我们对这些巨噬细胞在粘膜组织中发挥的多方面作用的理解， 因为肺还不完整肺是一个非常复杂的器官，有专门的结构， 充分的气体交换。肺微环境独特，对肺功能的恢复有着直接而重要的影响 免疫细胞尤其是巨噬细胞的数量目前，已经确定肺 含有两种不同的巨噬细胞群体，称为肺泡巨噬细胞（AM）和间质巨噬细胞（AM）。 巨噬细胞（IM）。肺巨噬细胞最重要的功能之一是调节炎症反应， 感染期间的途径，并允许在病原体被清除后解决炎症。的精确 巨噬细胞群体用来在体内完成这些关键功能的机制并不完善， 明白例如，巨噬细胞在调节病原体诱导的炎症中起关键作用， 呼吸道感染，如流感。流感感染导致世界范围内每年流行， 导致数千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 在体内引起感染诱导的炎症和病理的分子机制，以开发新的 减轻感染期间破坏性炎症的治疗策略。在这里，我们报告一个以前 仅局限于大细支气管周围的未表征的肺巨噬细胞亚群 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 初步数据显示，与其他基因相比，LAAM的转录基因特征是非常独特的。 与高表达调控基因的AM相关，因此，我们认为这些细胞在 在体内调节流感诱导的炎症。此外，LAAM的独特和排他性定位 这表明这些巨噬细胞可能在复合体中起着“看门人”的作用 肺的结构。因此，我们假设LAAM完全定义了一个新的巨噬细胞群体， 与其他肺巨噬细胞如AM不同，其独特的定位，显着的基因， 表达谱，以及对流感感染的显著反应使它们对于调节 免疫和组织稳态以及病原体诱导炎症。我们提出以下目标： 目的1：确定LAAM的个体发育、维持和细胞异质性;目的2：确定LAAM的 LAAM和AM感染后的生理意义;目的3：为了确定机制， 允许LAAM在稳态条件下或在呼吸道感染期间调节免疫/组织稳态。

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.