Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation
Kristofor E. Glinton, … , Guillermo Oliver, Edward B. Thorp
Kristofor E. Glinton, … , Guillermo Oliver, Edward B. Thorp
Published March 10, 2022
Citation Information: J Clin Invest. 2022;132(9):e140685. https://doi.org/10.1172/JCI140685.
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Research Article Inflammation Vascular biology

Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation

Abstract

Clearance of dying cells by efferocytosis is necessary for cardiac repair after myocardial infarction (MI). Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis after MI. Here, we report that defective efferocytosis by macrophages after experimental MI led to a reduction in cardiac lymphangiogenesis and Vegfc expression. Cell-intrinsic evidence for efferocytic induction of Vegfc was revealed after adding apoptotic cells to cultured primary macrophages, which subsequently triggered Vegfc transcription and VEGFC secretion. Similarly, cardiac macrophages elevated Vegfc expression levels after MI, and mice deficient for myeloid Vegfc exhibited impaired ventricular contractility, adverse tissue remodeling, and reduced lymphangiogenesis. These results were observed in mouse models of permanent coronary occlusion and clinically relevant ischemia and reperfusion. Interestingly, myeloid Vegfc deficiency also led to increases in acute infarct size, prior to the amplitude of the acute cardiac lymphangiogenesis response. RNA-Seq and cardiac flow cytometry revealed that myeloid Vegfc deficiency was also characterized by a defective inflammatory response, and macrophage-produced VEGFC was directly effective at suppressing proinflammatory macrophage activation. Taken together, our findings indicate that cardiac macrophages promote healing through the promotion of myocardial lymphangiogenesis and the suppression of inflammatory cytokines.

Authors

Kristofor E. Glinton, Wanshu Ma, Connor Lantz, Lubov S. Grigoryeva, Matthew DeBerge, Xiaolei Liu, Maria Febbraio, Mark Kahn, Guillermo Oliver, Edward B. Thorp

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Figure 1

Bone marrow–derived Cd36 is required for both the accumulation of cardiac antigens in MLNs and increased tubular LYVE1 staining after MI.

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Bone marrow–derived Cd36 is required for both the accumulation of cardia...
(A) Imaging of murine MLN cross-sections 3 days after ligation of the LAD artery. Macrophages (MΦ) from LysMCre-EGFP mice show EGFP signal, and cardiomyocyte debris from Myh6-mCherry–transgenic mice show red signal. Scale bar: 40 μm. (B) Chimeric Myh6-mCherry mice, deficient for bone marrow–derived Cd36, were subjected to coronary artery occlusion. Three days after MI (D3), MLNs were harvested, and flow cytometric analysis of Ly6g–CD11b+CD11c+ cells was performed. n = 5 per group. max, maximum. ***P < 0.0005, by 2-tailed, unpaired t test. (C) C57BL/6 mice were subjected to MI via coronary occlusion of the LAD artery. Representative immunofluorescence images were taken from 2 weeks after MI. Data display tubular LYVE1+ staining of the myocardial infarct border zone in Cd36–/– mice versus Cd36+/+ mice. Scale bar: 125 μm. (D) Border zone quantification of LYVE1+CD68– nuclei in Cd36fl/fl versus Cd36fl/fl LysMCre mice after MI. n = 5 per group. **P < 0.007, by 2-tailed, unpaired t test. (E) qPCR analysis of myocardial Vegfc in Cd36-deficient mice after MI. n = 5 per group. **P < 0.005 and ***P < 0.0001, by 2-way ANOVA followed by Tukey’s test. (F) Expression of VEGFC in cardiac macrophages with myeloid-specific deletion of Cd36 compared with controls 7 days after MI. n = 4–6 mice per group pooled from 2 independent experiments. *P < 0.05, by 2-tailed, unpaired t test.