Induction of cardiac angiogenesis requires killer cell lectin-like receptor 1 and α4β7 integrin expression by NK cells.
Recent findings indicate that NK cells are involved in cardiac repair following myocardial infarction. The aim of this study is to investigate the role NK cells in infarct angiogenesis and cardiac remodeling. In normal C57BL/6 mice, myelomonocytic inflammatory cells invaded infarcted heart within 24 h followed by a lymphoid/NK cell infiltrate by day 6, accompanied by substantial expression of IL-2, TNF-α, and CCL2. In contrast, NOD SCID mice had virtually no lymphoid cells infiltrating the heart and did not upregulate IL-2 levels. In vitro and in vivo, IL-2-activated NK cells promoted TNF-α-stimulated endothelial cell proliferation, enhanced angiogenesis and reduced fibrosis within the infarcted myocardium. Adoptive transfer of IL-2-activated NK cells to NOD SCID mice improved post-myocardial infarction angiogenesis. RNA silencing technology and neutralizing Abs demonstrated that this process involved α4β7 integrin/VCAM-1 and killer cell lectin-like receptor 1/N-cadherin-specific binding. In this study, we show that IL-2-activated NK cells reduce myocardial collagen deposition along with an increase in neovascularization following acute cardiac ischemia through specific interaction with endothelial cells. These data define a potential role of activated NK cells in cardiac angiogenesis and open new perspectives for the treatment of ischemic diseases.
Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Manaf
M
Bouchentouf
Kathy-Ann
KA
Forner
Jessica
J
Cuerquis
Véronique
V
Michaud
Jiamin
J
Zheng
Pierre
P
Paradis
Ernesto L
EL
Schiffrin
Jacques
J
Galipeau
D000818:Animals; D002450:Cell Communication / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016023:Integrins / Q000096:biosynthesis* / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018919:Neovascularization, Physiologic / Q000276:immunology*; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D016023:Integrins; D007376:Interleukin-2; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C071777:integrin alpha4beta7