Hif-1 alpha metabolically reprograms recruited alveolar macrophages to promote lung repair

Hif-1 α 通过代谢重新编程招募的肺泡巨噬细胞以促进肺修复

基本信息

批准号：
9309186
负责人：
William Janssen
金额：
$ 54.99万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2018-02-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9309186
关键词：
Acute Acute Lung Injury Address Affect Alveolar Alveolar Cell Alveolar Macrophages Alveolus Apoptosis Blood capillaries Capillary Endothelial Cell Cell Proliferation Cells Cessation of life Complex Data Defect Embryonic Development Endothelial Cells Endothelium Energy Metabolism Epithelial Epithelial Cells Functional disorder Gases Genes Genetic Transcription Glycolysis HIF1A gene Health Histologic Homeostasis Hypoxia Inducible Factor Impairment Inflammation Injury Life Lung Metabolic Metabolism Molecular Mus Oxidative Phosphorylation Pathologic Pathway Analysis Platelet-Derived Growth Factor Play Pneumonia Process Production Proliferating Recovery Recruitment Activity Respiratory physiology Role Site Stable Populations Structure Testing Therapeutic Intervention Time Tissues Vascular Endothelial Growth Factors Warburg Effect Wild Type Mouse aerobic glycolysis alveolar epithelium anaerobic glycolysis capillary cell injury differential expression functional restoration inflammatory lung disease injured lung injury lung repair macrophage meetings migration monocyte neutrophil programs repaired response to injury restoration self-renewal tissue repair tool transcriptome sequencing

项目摘要

PROJECT SUMMARY Pneumonia and acute inflammatory diseases of the lungs affect over 450 million people worldwide each year and result in over 4 million deaths. Pathologic hallmarks include neutrophil accumulation in the airspaces, injury to alveolar epithelial and endothelial cells, and resultant loss of epithelial-capillary integrity with impaired gas exchange. Accordingly, restoration of lung function requires repair of injured alveoli, replacement of injured epithelial and endothelial cells, and re-establishment of capillary barrier function. Macrophages are recognized as critical orchestrators of tissue repair, however the mechanisms that drive their programming are poorly understood. During health the airspaces are occupied by a stable population of resident alveolar macrophages (RAM) that arise during embryogenesis and self-renew throughout life. RAMs remain during inflammation but are joined by recruited macrophages (RecMΦ) that arise from circulating monocytes. These RecMΦ remain in the lung while lung structure and function are restored, and then undergo apoptosis leaving RAMs to once again populate the healthy airspaces. The contributions provided by RAM and RecMΦ to alveolar repair are largely unknown and represent an important barrier to advancement in the field. In order to address this unmet need, our group performed time-resolved RNA sequencing on RAMs and RecMΦ isolated from LPS treated mice during acute and resolving inflammation. Our data showed marked differences in the transcriptomal profiles of RAMs and RecMΦ at all time points studied, with over 50% of genes differentially expressed. Pathway analysis and functional studies demonstrated that RecMΦ produce high levels of epithelial and endothelial proliferative factors and suggested that RecMΦ are key orchestrators of tissue repair. Studies using CCR2 -/- mice, which have defects in monocyte migration and impaired accumulation of RecMΦ, further supported this concept; LPS treated CCR2-/- and wild type mice had equivalent degrees of lung injury, but CCR2-/- mice had reduced epithelial and endothelial proliferation and prolonged capillary barrier dysfunction. Transcriptomal and metabolic analyses suggested that HIF-1α transcription and stabilization were increased in RecMΦ and that HIF-1α induced metabolically reprograming the RecMΦ toward glycolysis. These data led us to hypothesize that RecMΦ are essential orchestrators of epithelial and endothelial cell proliferation following acute lung injury and that the relevant programming of RecMΦ is driven by HIF-1α and glycolytic energy metabolism. This will be tested in three Specific Aims. 1) Test the hypothesis that recruited macrophages are programed to stimulate proliferation of alveolar epithelial and endothelial cells following acute lung injury. 2) Test the hypothesis that glycolytic metabolism in recruited macrophages promotes their production of epithelial and endothelial proliferative factors and stimulates tissue repair. 3) Test the hypothesis that HIF-1α is responsible for metabolic reprogramming of recruited macrophages with enhanced anaerobic glycolysis and reduced oxidative phosphorylation.

项目摘要肺的肺炎和急性炎症性疾病每年影响全球超过4.5亿人并导致超过400万人死亡。病理标志包括中性粒细胞在空间中的积累，肺泡上皮和内皮细胞的损伤，以及由于受损而导致的上皮毛细血管完整性的损失天然气交换。根据肺功能的恢复，需要修复受伤的肺泡，更换受伤上皮细胞和内皮细胞，以及毛细血管屏障功能的重新建立。巨噬细胞被认可作为组织修复的关键编排，但是驱动其编程的机制很差理解齿。在健康期间，空域被稳定的居民肺泡巨噬细胞占据（RAM）在胚胎发生和自我更新过程中出现的（RAM）。公羊在炎症期间保留，但由循环单核细胞引起的招募巨噬细胞（RECMφ）连接。这些收集保留在肺结结构和功能时的肺恢复，然后进行凋亡，将RAM留给一次再次填充健康的空间。 RAM和RECMφ为肺泡修复提供的贡献是在很大程度上未知，代表了该领域发展的重要障碍。为了解决这个未定的需要，我们的小组在RAM上进行了时间分辨的RNA测序，并从经过的LPS分离出来急性和解决炎症期间的小鼠。我们显示的数据标志着转录组的差异在所有时间点研究的RAM和RECMφ的轮廓，超过50％的基因表达了超过50％。途径分析和功能研究表明，循环产生了高水平的上皮和内皮增生剂，并建议recmφ是组织修复的关键编排者。研究使用CCR2 - / - 小鼠，这些小鼠在单核细胞迁移和RECMφ加速度受损中存在缺陷，进一步支持这个概念； LPS处理的CCR2 - / - 和野生型小鼠的肺损伤程度相等，但 CCR2 - / - 小鼠减少了上皮和内皮增殖，毛细血管屏障功能障碍延长。转录组和代谢分析表明，HIF-1α转录和稳定在 RECMφ并认为HIF-1α诱导代谢重新编程，以糖酵解的糖酵解。这些数据导致我们假设recmφ是上皮和内皮细胞增殖的必要编排者急性肺损伤，相关的RECMφ编程是由HIF-1α和糖酵解能驱动的代谢。这将以三个具体目标进行测试。 1）检验招募巨噬细胞的假设是编程以刺激急性肺损伤后肺泡上皮和内皮细胞的增殖。 2）检验以下假设，即招募巨噬细胞中的糖酵解代谢会促进其上皮的产生和内皮增生剂并刺激组织修复。 3）检验HIF-1α的假设负责用厌氧性糖酵解和氧化物磷酸化降低。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Apoptotic cell clearance and fibrotic lung disease.

DOI：
10.1183/09031936.00020612
发表时间：
2012-08
期刊：
The European respiratory journal
影响因子：
0
作者：
Janssen WJ;Morimoto K
通讯作者：
Morimoto K

Kinetics of the angiogenic response in lung endothelium following acute inflammatory injury with bleomycin.

DOI：
10.3109/01902148.2014.938202
发表时间：
2014-10
期刊：
Experimental lung research
影响因子：
1.7
作者：
Yunt ZX;Mohning MP;Barthel L;Kearns MT;Tuder RM;Hyde DM;Henson PM;Janssen WJ
通讯作者：
Janssen WJ

Neutrophil-mediated T-Cell Suppression in Influenza: Novel Finding Raising Additional Questions.

流感中中性粒细胞介导的 T 细胞抑制：新发现引发了更多问题。

DOI：
10.1165/rcmb.2017-0425ed
发表时间：
2018
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
Zemans,RachelL
通讯作者：
Zemans,RachelL

Defective efferocytosis by alveolar macrophages in IPF patients.

DOI：
10.1016/j.rmed.2012.08.020
发表时间：
2012-12
期刊：
RESPIRATORY MEDICINE
影响因子：
4.3
作者：
Morimoto, Konosuke;Janssen, William J.;Terada, Mayumi
通讯作者：
Terada, Mayumi

Selective and inducible targeting of CD11b+ mononuclear phagocytes in the murine lung with hCD68-rtTA transgenic systems.

使用 hCD68-rtTA 转基因系统选择性和诱导性靶向小鼠肺中的 CD11b 单核吞噬细胞。

DOI：
10.1152/ajplung.00141.2016
发表时间：
2016
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
McCubbrey,AlexandraL;Barthel,Lea;Mould,KaraJ;Mohning,MichaelP;Redente,ElizabethF;Janssen,WilliamJ
通讯作者：
Janssen,WilliamJ