Open AccessAAV-Mediated Expression of Human VEGF, TNF-α, and IL-6 Induces Retinal Pathology in Mice
Author(s) -
Carina Marianne Weigelt,
Holger Fuchs,
Tanja Schönberger,
Birgit Stierstorfer,
Benjamin Strobel,
Thorsten Lamla,
Thomas Ciossek,
Remko A. Bakker,
Norbert Redemann
Publication year - 2021
Publication title -
translational vision science and technology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.508
H-Index - 21
ISSN - 2164-2591
DOI - 10.1167/tvst.10.11.15
Subject(s) - proinflammatory cytokine , retina , pathology , medicine , inflammation , retinal , vascular endothelial growth factor , tumor necrosis factor alpha , fibrosis , immunology , biology , cancer research , ophthalmology , neuroscience , vegf receptors
Purpose Retinopathies display complex pathologies, including vasculopathies, inflammation, and fibrosis, leading ultimately to visual impairment. However, animal models accurately reflecting these pathologies are lacking. In this study, we evaluate the suitability of using Adeno-associated virus (AAV)-mediated long-term expression of cytokines to establish retinal pathology in the murine retina. Methods We administered recombinant, Müller-glia targeted AAV-ShH10 into the mouse vitreous to induce retinal expression of either human vascular endothelial growth factor (VEGF)-A 165 , tumor necrosis factor alpha (TNF-α), or interleukin-6 (IL-6) and evaluated consequent effects by optical coherence tomography, fluorescein angiography, and histology. Results Intravitreal injection of AAVs resulted in rapid and stable expression of the transgenes within 1 to 6 weeks. Akin to the role of VEGF-A in wet age-related macular degeneration, expression of VEGF-A led to several vasculopathies in mice, including neovascularization and vascular leakage. In contrast, the expression of the proinflammatory cytokines TNF-α or IL-6 induced retinal inflammation, as indicated by microglial activation. Furthermore, the expression of TNF-α, but not of IL-6, induced immune cell infiltration into the vitreous as well as vasculitis, and subsequently induced the development of fibrosis and epiretinal membranes. Conclusions In summary, the long-term expression of human VEGF-A 165 , TNF-α, or IL-6 in the mouse eye induced specific pathologies within 6 weeks that mimic different aspects of human retinopathies. Translational Relevance AAV-mediated expression of human genes in mice is an attractive approach to provide valuable insights into the underlying molecular mechanisms causing retinopathies and is easily adaptable to other genes and preclinical species supporting drug discovery for retinal diseases.