CNTF Prevents Development of Outer Retinal Neovascularization Through Upregulation of CxCl10

Abstract

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 Müller 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 Müller 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 Müller cells.

Regulations of Retinal Inflammation: Focusing on Müller Glia

“…Only with the activation of the gp130 in MG, can CNTF-mediated protection of photoreceptors be observed ( Rhee et al, 2013 ). In response to CNTF treatment, the JAK/STAT3 signaling pathway, which plays a crucial role in the mediation of inflammatory responses, is activated in MG with reduced outer retinal neovascularization ( Bucher et al, 2020 ). CNTF protects the retinal neurons from toxic insult but also suppresses damage-induced proliferation of MG in the retina of zebrafish ( Fischer et al, 2004 ).…”

Comparison of Intraocular Cytokine Levels of Choroidal Neovascularization Secondary to Different Retinopathies

“…In our study, the IP-10 level was elevated in all CNV groups except the nCSC group. IP-10 was capable of inhibiting both retinal and choroidal neovascularization as an inflammationrelated chemokine (25). However, the molecular mechanism remains unknown.…”

Comparative transcriptome analysis of human and murine choroidal neovascularization identifies fibroblast growth factor inducible-14 as phylogenetically conserved mediator of neovascular age-related macular degeneration

“…So far, the laser-induced CNV mouse model was extensively used to mimic the disease in vivo allowing the identification and evaluation of novel mediators of CNV development (Bucher et al, 2020;Lange et al, 2016;Schlecht et al, 2020b;Wang et al, 2013). However, an unbiased comparison of the transcriptional landscapes between murine and human CNV is still lacking but of significant importance for the interpretation of the mouse model and the translation of preclinical findings into novel clinical treatment regimens.…”