Julian Wolf1, Anja Schlecht2, Dennis-Dominik Rosmus3, Stefaniya Boneva1, Hansjürgen Agostini1, Günther Schlunck1, Peter Wieghofer4, Clemens Lange5. 1. Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Germany. 2. Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Germany; Institute of Anatomy, Wuerzburg University, Wuerzburg, Germany. 3. Institute of Anatomy, Leipzig University, Leipzig, Germany. 4. Institute of Anatomy, Leipzig University, Leipzig, Germany; Cellular Neuroanatomy, Institute of Theoretical Medicine, Medical Faculty, University of Augsburg, Augsburg, Germany. 5. Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Germany; Ophtha-Lab, Department of Ophthalmology, St. Franziskus Hospital Muenster, Muenster, Germany. Electronic address: clemens.lange@augen-franziskus.de.
Abstract
BACKGROUND: Visual outcome of patients with neovascular age-related macular degeneration has significantly improved during the last years following the introduction of anti-vascular endothelial growth factor (VEGF) therapy. However, about one third of patients show persistent exudation and decreasing visual acuity despite recurrent anti-VEGF treatment, which implies a role of other, still unknown proangiogenic mediators. METHODS: The present study applied transcriptional profiling of human and mouse (C57BL/6J wildtype) choroidal neovascularization (CNV) membranes each with reference to healthy control tissue to identify yet unrecognized mediators of CNV formation. Key factors were further investigated by immunohistochemistry as well as by intravitreal inhibition experiments and multiplex protein assays in the laser-induced CNV mouse model. FINDINGS: Transcriptional profiles of CNV membranes were characterized by enhanced activation of blood vessel development, cytoskeletal organization, and cytokine production, with angiogenesis and wound healing processes predominating in humans and activation of immune processes in mice. Besides several species-specific factors, 95 phylogenetically conserved CNV-associated genes were detected, among which fibroblast growth factor inducible-14 (FN14), a member of the tumor necrosis factor (TNF) receptor family, was identified as a key player of CNV formation. Blocking the pathway by intravitreal injection of a FN14 decoy receptor modulated the cytokine profile - most notably IL-6 - and led to a significant reduction of CNV size in vivo. INTERPRETATION: This study characterizes the transcriptome of human and mouse CNV membranes in an unprejudiced manner and identifies FN14 as a phylogenetically conserved mediator of CNV formation and a promising new therapeutic target for neovascular AMD. FUNDING: This study was funded by the Helmut Ecker Foundation and the Volker Homann Foundation.
BACKGROUND: Visual outcome of patients with neovascular age-related macular degeneration has significantly improved during the last years following the introduction of anti-vascular endothelial growth factor (VEGF) therapy. However, about one third of patients show persistent exudation and decreasing visual acuity despite recurrent anti-VEGF treatment, which implies a role of other, still unknown proangiogenic mediators. METHODS: The present study applied transcriptional profiling of human and mouse (C57BL/6J wildtype) choroidal neovascularization (CNV) membranes each with reference to healthy control tissue to identify yet unrecognized mediators of CNV formation. Key factors were further investigated by immunohistochemistry as well as by intravitreal inhibition experiments and multiplex protein assays in the laser-induced CNV mouse model. FINDINGS: Transcriptional profiles of CNV membranes were characterized by enhanced activation of blood vessel development, cytoskeletal organization, and cytokine production, with angiogenesis and wound healing processes predominating in humans and activation of immune processes in mice. Besides several species-specific factors, 95 phylogenetically conserved CNV-associated genes were detected, among which fibroblast growth factor inducible-14 (FN14), a member of the tumor necrosis factor (TNF) receptor family, was identified as a key player of CNV formation. Blocking the pathway by intravitreal injection of a FN14 decoy receptor modulated the cytokine profile - most notably IL-6 - and led to a significant reduction of CNV size in vivo. INTERPRETATION: This study characterizes the transcriptome of human and mouse CNV membranes in an unprejudiced manner and identifies FN14 as a phylogenetically conserved mediator of CNV formation and a promising new therapeutic target for neovascular AMD. FUNDING: This study was funded by the Helmut Ecker Foundation and the Volker Homann Foundation.
Authors: Yan Gong; Yohei Tomita; Matthew L Edin; Anli Ren; Minji Ko; Jay Yang; Edward Bull; Darryl C Zeldin; Ann Hellström; Zhongjie Fu; Lois E H Smith Journal: Metabolism Date: 2022-07-19 Impact factor: 13.934
Authors: Gökhan Güner; Marlene Aßfalg; Kai Zhao; Tobias Dreyer; Shibojyoti Lahiri; Yun Lo; Bianca Ionela Slivinschi; Axel Imhof; Georg Jocher; Laura Strohm; Christian Behrends; Dieter Langosch; Holger Bronger; Christopher Nimsky; Jörg W Bartsch; Stanley R Riddell; Harald Steiner; Stefan F Lichtenthaler Journal: EMBO Mol Med Date: 2022-09-07 Impact factor: 14.260