Novel lung resident interstitial macrophage subset with distinct localization and polarization

具有独特定位和极化的新型肺驻留间质巨噬细胞亚群

• 批准号: 10327097
• 负责人: Kamal Mohan Khanna
• 金额: $ 7.89万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327097
• 关键词: Adult; Alveolar Macrophages; Alveolus; Attention; Blood; Bronchioles; Cells; Cessation of life; Clinical; Complex; Data; Development; Environment; Epidemic; Gases; Gatekeeping; Gene Expression Profile; Generations; Genetic Transcription; Geography; Goals; Growth; Heterogeneity; Homeostasis; Hospitalization; Human; Immune; Immune response; Immunologics; Immunology; Infection; Infection prevention; Inflammation; Inflammatory; Influenza; Innate Immune Response; Intervention; Invaded; Lead; Life; Lung; Lymph; Lymphoid; Lymphoid Tissue; Maintenance; Malpighian corpuscles; Mediating; Molecular; Mucous Membrane; Mus; Myeloid Cells; Organ; Outcome; Paper; Pathology; Pathway interactions; Phenotype; Physiological; Play; Population; Positioning Attribute; Proliferating; Property; Reaction; Regulation; Regulator Genes; Reporting; Research; Resolution; Respiratory Tract Infections; Role; Science; Sentinel; Shapes; Structure; Testing; Therapeutic Intervention; Tissues; Viral; Yolk Sac; adverse outcome; fetal; genetic signature; in vivo; inflammatory lung disease; influenza infection; influenzavirus; insight; interstitial; macrophage; monocyte; novel; novel therapeutic intervention; pathogen; pulmonary function; residence; respiratory infection virus; response; targeted treatment

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.

抽象的 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显现 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逐渐显现。 因为肺仍然不完整，肺是一个非常复杂的器官，具有特殊的结构。 充足的气体交换是肺部微环境独特的，具有直接而重要的影响。 目前，已明确肺中存在免疫细胞，特别是巨噬细胞群。 拥有两种不同的巨噬细胞群，称为肺泡巨噬细胞 (AM) 和间质巨噬细胞 肺巨噬细胞（IM）最重要的功能之一是调节炎症。 感染期间的途径并允许在病原体被清除后解决炎症。 巨噬细胞群在体内完成这些关键功能的机制尚不完善 例如，巨噬细胞在调节病原体诱导的炎症过程中发挥着关键作用。 呼吸道感染，例如流感感染，会导致全球范围内的年度流行病。 数以千计的死亡和住院病例是由组织损伤引起的。 因此，迫切需要了解病毒引起的免疫反应。 引起体内感染引起的炎症和病理的分子机制，以便开发新的 在此我们报告了先前的减轻感染期间破坏性炎症的治疗策略。 肺巨噬细胞的未表征子集，仅位于大细支气管周围 我们将这些细胞称为大气道相关间质巨噬细胞（LAAM）。 初步数据表明，相比之下，LAAM 的转录基因特征异常独特 调节基因高表达的AMs，因此，我们相信这些细胞在 调节流感引起的体内炎症此外，LAAM 的独特定位。 到大气道表明这些巨噬细胞可能在复合体中发挥“看门人”功能 因此，我们发现 LAAM 完全定义了一个新的巨噬细胞群。 区别于AM等其他肺巨噬细胞，其独特的定位、显着的基因 表达谱以及对流感感染的显着反应使它们对于调节至关重要 我们提出以下目标： 目标 1：确定 LAAM 的个体发育、维持和细胞异质性；目标 2：确定 LAAM 的个体发育、维持和细胞异质性； 感染后 LAAM 和 AM 的生理意义；目标 3：确定其机制 允许 LAAM 在稳态条件下或呼吸道感染期间调节免疫/组织稳态。