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Felicitas Bucher, Edith Aguilar, Kyle V Marra, Andreas Stahl, Martin Friedlander; CxCl10 mediates CNTF inhibition of outer retinal neovascularization. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5327.
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Ciliary neurotrophic factor (CNTF) is a well-studied neurotrophic agent and strong activator of the Jak-Stat3 signaling pathway. Our previous work showed that CNTF-induced Stat3 signaling reduces retinal neovascularization in a model of oxygen-induced retinopathy through a direct effect on retinal vascular endothelial cells. In this study, we test the effect of CNTF on outer retinal and choroidal neovascularization. We further evaluate the role of C-X-C motif chemokine 10 (CxCl10), a well-established Stat3 target that ranks among the most strongly upregulated genes in response to CNTF treatment.
The VLDLR-/- mouse model and the laser-CNV model were used to assess the effect of CNTF and CxCl10 on outer retinal neovascularization. In both models, mice received a one-time intravitreal injection of recombinant CNTF or CxCl10, on P12 in the VLDLR-/- model and 1 day after laser in the CNV model. The extent of neovascular lesions was assessed 6 days post injection. qPCR analysis was used to identify Stat3 downstream targets affected by CNTF treatment. Conditioned media of CNTF-treated primary Müller cells were screened for changes in angiogenic factors using a proteome array.
CNTF treatment significantly reduced intraretinal tuft formation in the VLDLR-/- mouse model (N=16, p=0,001) as well as choroidal neovascularization in the laser-CNV model (N=20, p=0,0005). In CNTF-treated retinas, activated Stat3 signaling was identified in vascular endothelial cells and Müller cells. CNTF-treatment significantly increased Cxcl10 mRNA and secreted protein levels both in vivo and in vitro. In vivo experiments confirmed that intravitreal injections of recombinant CxCl10 significantly reduced intraretinal tuft formation in the VLDLR-/- model at P18 (N=19, p=0,002).
These data suggest that the potent anti-angiogenic effect of CNTF is not limited to the inner retinal but also applies to the outer retinal and choroidal layers. While the direct effect of CNTF on retinal vascular endothelial cells may play an important role in neovascular changes of the inner retina, increased secretion of Cxcl10 from retinal Müller cells may represent how CNTF treatment indirectly affects vascular endothelial cells, particularly in the outer retina.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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