CNTF Prevents Development of Outer Retinal Neovascularization Through Upregulation of CxCl10

PURPOSE. Ciliary neurotrophic factor (CNTF) is a well-characterized neurotrophic factor currently in clinical trials for the treatment of macular telangiectasia type II. Our previous work showed that CNTF-induced STAT3 signaling is a potent inhibitor of pathologic preretinal neovascular tuft formation in the mouse model of oxygen-induced retinopathy. In this study, we investigated the effect of CNTF on outer retinal and choroidal angiogenesis and the mechanisms that underpin the observed decrease in outer retinal neovascularization following CNTF treatment. METHODS. In the Vldlr(-/-) and laser-CNV mouse models, mice received a one-time injection (on postnatal day [P] 12 in the Vldlr(-/-) model and 1 day after laser in the Choroidal Neovascularization (CNV) model) of recombinant CNTF or CxCl10, and the extent of neovascular lesions was assessed 6 days posttreatment. STAT3 downstream targets affected by CNTF treatment were identified using quantitative PCR analysis. A proteome array was used to compare media conditioned by CNTF-treated and control-treated primary Muller cells to screen for CNTF-induced changes in secreted angiogenic factors. RESULTS. Intravitreal treatment with recombinant CNTF led to significant reduction in neovascularization in the Vldlr(-/-) and laser-CNV mouse models. Treatment effect in the Vldlr(-/-) was long-lasting but time sensitive, requiring intravitreal treatment before P19. Mechanistic workup in vitro as well as in vivo confirmed significant activation of the STAT3-signaling pathway in Muller cells in response to CNTF treatment and upregulation of CxCl10. Intravitreal injections of recombinant CxCl10 significantly reduced outer retinal neovascularization in vivo in both the Vldlr(-/-) and laser-CNV mouse models. CONCLUSIONS. CNTF treatment indirectly affects outer retinal and choroidal neovascularization by inducing CxCl10 secretion from retinal Muller cells.