The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction
Joaquim Miguel Vieira, … , David G. Jackson, Paul R. Riley
Joaquim Miguel Vieira, … , David G. Jackson, Paul R. Riley
Published July 9, 2018
Citation Information: J Clin Invest. 2018;128(8):3402-3412. https://doi.org/10.1172/JCI97192.
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Research Article Inflammation Vascular biology

The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction

Abstract

Myocardial infarction (MI) arising from obstruction of the coronary circulation engenders massive cardiomyocyte loss and replacement by non-contractile scar tissue, leading to pathological remodeling, dysfunction, and ultimately heart failure. This is presently a global health problem for which there is no effective cure. Following MI, the innate immune system directs the phagocytosis of dead cell debris in an effort to stimulate cell repopulation and tissue renewal. In the mammalian adult heart, however, the persistent influx of immune cells, coupled with the lack of an inherent regenerative capacity, results in cardiac fibrosis. Here, we reveal that stimulation of cardiac lymphangiogenesis with VEGF-C improves clearance of the acute inflammatory response after MI by trafficking immune cells to draining mediastinal lymph nodes (MLNs) in a process dependent on lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Deletion of Lyve1 in mice, preventing docking and transit of leukocytes through the lymphatic endothelium, results in exacerbation of chronic inflammation and long-term deterioration of cardiac function. Our findings support targeting of the lymphatic/immune cell axis as a therapeutic paradigm to promote immune modulation and heart repair.

Authors

Joaquim Miguel Vieira, Sophie Norman, Cristina Villa del Campo, Thomas J. Cahill, Damien N. Barnette, Mala Gunadasa-Rohling, Louise A. Johnson, David R. Greaves, Carolyn A. Carr, David G. Jackson, Paul R. Riley

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Figure 5

Adoptive transfer of splenic GFP+ monocytes confirms immune cell clearance to MLNs after MI.

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Adoptive transfer of splenic GFP+ monocytes confirms immune cell clearan...
(A) Schematic of the adoptive cell transfer approach using hCD68-EGFP transgenic mice as splenic GFP+ monocyte donor and recipient C57BL/6 adult mice receiving intramyocardial delivery of labeled monocytes at the time of LAD ligation, to assess immune cell trafficking to MLNs. (B–G) GFP (red) and CD68 (green) immunostaining (macrophage marker) of tissue sections documenting engraftment of CD68+GFP+ monocytes within the injury area at 7 days after MI (white arrowheads). No GFP-labeled cells were detected in sham-operated animals (F and G). (C–E) Magnified views of box shown in B. (G) Magnified view of box shown in F. DAPI (blue) labels cell nuclei. (H–M) GFP (red) and CD68 (green) immunostaining of tissue sections derived from MLNs of MI (H–K) and sham-operated (L–M) animals, indicating the presence of cleared CD68+GFP+ phagocytic cells (white arrowheads) in MLNs after MI. (I, J, and K) Magnified views of box in H. (M) Magnified view of box in L. DAPI (blue) labels cell nuclei. Scale bars: 100 μm; except C, G, I, and M, 20 μm.