Mapping macrophage polarization over the myocardial infarction time continuum

• Published in: Basic research in cardiology Vol. 113; no. 4; pp. 26 - 18
• Main Authors: Mouton, Alan J., DeLeon-Pennell, Kristine Y., Rivera Gonzalez, Osvaldo J., Flynn, Elizabeth R., Freeman, Tom C., Saucerman, Jeffrey J., Garrett, Michael R., Ma, Yonggang, Harmancey, Romain, Lindsey, Merry L.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-07-2018; Springer Nature B.V
• Subjects: Animals; Cardiology; Cell Plasticity - genetics; Cell Proliferation; Cells, Cultured; Collagen (type I); Coronary artery; Disease Models, Animal; Energy Metabolism; Extracellular matrix; Extracellular Matrix - genetics; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Flow Cytometry; Gene expression; Gene Expression Profiling; Gene sequencing; Genes; Genotype; Heart; Heart attacks; Heart diseases; Inflammation; Inflammation Mediators - metabolism; Macrophages; Macrophages - metabolism; Macrophages - pathology; Male; Medicine; Medicine & Public Health; Metabolism; Mice, Inbred C57BL; Mitochondria; Monocytes; Myocardial infarction; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardium - metabolism; Myocardium - pathology; Original Contribution; Oxidative phosphorylation; Phagocytosis; Phenotype; Phosphorylation; Polarization; Ribonucleic acid; RNA; Rodents; Time Factors; Transcriptome; Ventricular Function, Left - genetics; Ventricular Remodeling - genetics; Myocardial infarction; LV remodeling; RNA-Seq; Transcriptome; Macrophage
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-018-0686-x

In response to myocardial infarction (MI), cardiac macrophages regulate inflammation and scar formation. We hypothesized that macrophages undergo polarization state changes over the MI time course and assessed macrophage polarization transcriptomic signatures over the first week of MI. C57BL/6 J male mice (3–6 months old) were subjected to permanent coronary artery ligation to induce MI, and macrophages were isolated from the infarct region at days 1, 3, and 7 post-MI. Day 0, no MI resident cardiac macrophages served as the negative MI control. Whole transcriptome analysis was performed using RNA-sequencing on
n
 = 4 pooled sets for each time. Day 1 macrophages displayed a unique pro-inflammatory, extracellular matrix (ECM)-degrading signature. By flow cytometry, day 0 macrophages were largely F4/80
high
Ly6C
low
resident macrophages, whereas day 1 macrophages were largely F4/80
low
Ly6C
high
infiltrating monocytes. Day 3 macrophages exhibited increased proliferation and phagocytosis, and expression of genes related to mitochondrial function and oxidative phosphorylation, indicative of metabolic reprogramming. Day 7 macrophages displayed a pro-reparative signature enriched for genes involved in ECM remodeling and scar formation. By triple in situ hybridization, day 7 infarct macrophages in vivo expressed collagen I and periostin mRNA. Our results indicate macrophages show distinct gene expression profiles over the first week of MI, with metabolic reprogramming important for polarization. In addition to serving as indirect mediators of ECM remodeling, macrophages are a direct source of ECM components. Our study is the first to report the detailed changes in the macrophage transcriptome over the first week of MI.