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Invest Ophthalmol Vis Sci. 2014 May 2;55(5):2885-92. doi: 10.1167/iovs.14-14093.

A novel pro-angiogenic function for interferon-γ-secreting natural killer cells.

Author information

1
Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.

Abstract

PURPOSE:

To explore the function of natural killer (NK) cells in inflammatory angiogenesis in mice.

METHODS:

To study ocular angiogenic responses we used the cornea BFGF micropellet and the laser-induced choroidal neovascularization (CNV) mouse models (C57BL/6). To deplete NK cells in these models, we injected an anti-NK1.1 antibody or an isotype antibody as a control. Corneas or choroids were immunohistochemically stained for blood vessels (CD31), macrophages (F4/80), or CNV (isolectin-IB4). Vascular endothelial growth factors (VEGF), IFN-γ, or TNF-α levels were measured by real-time quantitative PCR (qPCR) or flow cytometry. A coculture assay of macrophages, NK cells, and human umbilical vein endothelial cells (HUVECs) was analyzed morphometrically to examine the ability of NK cells to induce angiogenesis in vitro.

RESULTS:

Our data demonstrate that in vivo depletion of NK cells leads to a significant reduction of corneal angiogenesis and CNV. Furthermore, NK cell depletion reduces macrophage infiltration into the cornea and mRNA expression levels of VEGF-A, VEGF-C, and VEGFR3 at day 7 after micropellet insertion. In the laser-induced CNV model, our data show that NK cell depletion leads to decreased areas of CNV and significantly reduced mRNA expression of VEGFs and IFN-γ in the choroid. An in vitro coculture assay shows an IFN-γ-dependent increase in VEGF expression levels, thereby increasing endothelial cell proliferation.

CONCLUSIONS:

Our findings demonstrate a novel pro-angiogenic function for NK cells, indicating that IFN-γ-secreting NK cells can induce angiogenesis by promoting enhanced VEGF expression by macrophages.

KEYWORDS:

NK cells; endothelial cells; interferons; macrophages; neovascularization

PMID:
24713481
PMCID:
PMC4010366
DOI:
10.1167/iovs.14-14093
[Indexed for MEDLINE]
Free PMC Article
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