CNTF Prevents Development of Outer Retinal Neovascularization Through Upregulation of CxCl10
Felicitas Bucher1,2, Edith Aguilar1, Kyle V Marra1,3
1Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States.
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.
Insights
Ciliary neurotrophic factor (CNTF) reduces retinal neovascularization by activating STAT3 signaling in Müller cells, leading to CxCl10 secretion. This study reveals CNTF
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Ciliary neurotrophic factor (CNTF) is investigated for macular telangiectasia type II.
- CNTF-induced STAT3 signaling inhibits preretinal neovascular tuft formation.
- Previous research demonstrated CNTF's inhibitory effect on retinopathy.
Purpose of the Study:
- To investigate CNTF's effect on outer retinal and choroidal angiogenesis.
- To elucidate the mechanisms behind CNTF's reduction of outer retinal neovascularization.
Main Methods:
- Mice models (Vldlr-/- and laser-CNV) received intravitreal recombinant CNTF or CxCl10.
- Neovascular lesions were assessed 6 days posttreatment.
- STAT3 downstream targets and secreted angiogenic factors were analyzed using qPCR and proteome arrays.
Main Results:
- Intravitreal CNTF significantly reduced neovascularization in both mouse models.
- CNTF treatment activated STAT3 signaling and upregulated CxCl10 in Müller cells.
- Intravitreal CxCl10 also significantly reduced outer retinal neovascularization.
Conclusions:
- CNTF indirectly reduces outer retinal and choroidal neovascularization.
- CNTF induces CxCl10 secretion from retinal Müller cells, mediating the anti-angiogenic effect.
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