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

• 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
• 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

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.

项目总结

项目成果

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

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

Lung disease in rheumatoid arthritis.

• DOI: 10.1016/j.rdc.2014.12.004
• 发表时间: 2015-05
• 期刊: RHEUMATIC DISEASE CLINICS OF NORTH AMERICA
• 影响因子: 2.3
• 作者: Yunt, Zulma X.;Solomon, Joshua J.
• 通讯作者: Solomon, Joshua J.

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
• 作者: McCubbrey,AlexandraL;Barthel,Lea;Mould,KaraJ;Mohning,MichaelP;Redente,ElizabethF;Janssen,WilliamJ
• 通讯作者: Janssen,WilliamJ