Abstract
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 F4/80highLy6Clow resident macrophages, whereas day 1 macrophages were largely F4/80lowLy6Chigh 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.
Highlights
Myocardial infarction (MI) invokes a cardiac wound healing response that involves early initiation of inflammation, followed by robust scar formation in the infarct area
Mice were injected with a FITC-F4/80 antibody (Biolegend, San Diego, CA, 123107, 200 μg/kg) through the jugular vein at 24 h post-MI and killed at day 3 post-MI
Cardiac physiology was impaired after MI, with left ventricle (LV) infarct wall thinning and dilatation evident beginning at day 1 after MI (Supplemental Fig. 2c–e)
Summary
Myocardial infarction (MI) invokes a cardiac wound healing response that involves early initiation of inflammation, followed by robust scar formation in the infarct area. The macrophage is a key regulator of cardiac remodeling, providing both strong pro-inflammatory signals early and reparative cues later [13, 24, 25, 41, 44]. Basic Research in Cardiology (2018) 113:26 release of pro-inflammatory cytokines such as interleukin (IL)-1β, a key regulator of post-MI inflammation [70]. Resident cardiac macrophages express high levels of the myeloid marker CD11b, as well as canonical macrophage markers including CD14, CD86, CX3CR1, F4/80, and MHC-II, and display an anti-inflammatory M2 phenotype [63]. Following MI, F4/80highLy6Clow resident macrophages are rapidly replaced by pro-inflammatory infiltrating F4/80lowLy6Chigh monocytes that are C CR2high [22]; by post-MI day 7, the macrophage phenotype shifts to a predominantly anti-inflammatory/pro-reparative M2 phenotype
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