CNTF Prevents Development of Outer Retinal Neovascularization Through Upregulation of CxCl10.

Animals Blotting, Western Cells, Cultured Chemokine CXCL10 / metabolism Choroidal Neovascularization / metabolism Ciliary Neurotrophic Factor / therapeutic use Disease Models, Animal Enzyme-Linked Immunosorbent Assay Ependymoglial Cells Immunohistochemistry Laser Coagulation Mice Mice, Inbred C57BL RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Retinal Neovascularization / metabolism STAT3 Transcription Factor / metabolism Up-Regulation

Journal

Investigative ophthalmology & visual science
ISSN: 1552-5783
Titre abrégé: Invest Ophthalmol Vis Sci
Pays: United States
ID NLM: 7703701

Informations de publication

Date de publication:
03 08 2020
Historique:
entrez: 12 8 2020
pubmed: 12 8 2020
medline: 2 1 2021
Statut: ppublish

Résumé

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. 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. 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. CNTF treatment indirectly affects outer retinal and choroidal neovascularization by inducing CxCl10 secretion from retinal Müller cells.

Identifiants

DOI: 10.1167/iovs.61.10.20 PMID: 32780864 PMC: PMC7441336
pubmed: 32780864
pii: 2770627
doi: 10.1167/iovs.61.10.20
pmc: PMC7441336
doi:

Substances chimiques

Chemokine CXCL10 0
Ciliary Neurotrophic Factor 0
Cxcl10 protein, mouse 0
RNA, Messenger 0
STAT3 Transcription Factor 0
Stat3 protein, mouse 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

20

Subventions

Organisme : NEI NIH HHS
ID : F30 EY029141
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007198
Pays : United States
Organisme : NEI NIH HHS
ID : R24 EY022025
Pays : United States

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Auteurs

Felicitas Bucher (F)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States.
Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Edith Aguilar (E)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States.

Kyle V Marra (KV)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States.
Department of Bioengineering, University of California, San Diego, San Diego, California, United States.

Julian Rapp (J)

Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Jakob Arnold (J)

Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Sophia Diaz-Aguilar (S)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States.
Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Clemens Lange (C)

Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Hansjürgen Agostini (H)

Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Günther Schlunck (G)

Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Andreas Stahl (A)

Department of Ophthalmology, University Medical Center Greifswald, Greifswald, Germany.

Martin Friedlander (M)

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States.
The Lowy Medical Research Institute, La Jolla, California, United States.

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › CNTF Prevents Development of Outer Retinal...
Recherchemedicale.com › Techniques d'investigation › Techniques de sonde moléculaire › Dosage immunologique › Immunotransfert › Technique de Western › CNTF Prevents Development of Outer Retinal...
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Recherchemedicale.com › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Chimiokines › Chimiokines CXC › Chimiokine CXCL10 › CNTF Prevents Development of Outer Retinal...
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