title: Interferon-beta signaling in retinal mononuclear phagocytes attenuates pathological neovascularization.
abstract: Age-related macular degeneration (AMD) is a leading cause of vision loss among the elderly. AMD pathogenesis involves chronic activation of the innate immune system including complement factors and microglia/macrophage reactivity in the retina. Here, we show that lack of interferon-β signaling in the retina accelerates mononuclear phagocyte reactivity and promotes choroidal neovascularization (CNV) in the laser model of neovascular AMD Complete deletion of interferon-α/β receptor (Ifnar) using Ifnar1(-/-) mice significantly enhanced early microglia and macrophage activation in lesion areas. This triggered subsequent vascular leakage and CNV at later stages. Similar findings were obtained in laser-treated Cx3cr1(Cre) (ER):Ifnar1(fl/fl) animals that allowed the tamoxifen-induced conditional depletion of Ifnar in resident mononuclear phagocytes only. Conversely, systemic IFN-β therapy of laser-treated wild-type animals effectively attenuated microgliosis and macrophage responses in the early stage of disease and significantly reduced CNV size in the late phase. Our results reveal a protective role of Ifnar signaling in retinal immune homeostasis and highlight a potential use for IFN-β therapy in the eye to limit chronic inflammation and pathological angiogenesis in AMD.
authors.affiliation: Retinal Immunology Laboratory (RIL), Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Lückoff
authors.affiliation: Retinal Immunology Laboratory (RIL), Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Caramoy
authors.affiliation: Retinal Immunology Laboratory (RIL), Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Scholz
authors.affiliation: Institute of Neuropathology and BIOSS Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.affiliation: Retinal Immunology Laboratory (RIL), Department of Ophthalmology, University of Cologne, Cologne, Germany thomas.langmann@uk-koeln.de.
authors.forename: Thomas
authors.identifier: 0000-0001-6826-529X
authors.initials: T
authors.lastname: Langmann
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016899:Interferon-beta / Q000378:metabolism*; D008262:Macrophage Activation; D008268:Macular Degeneration / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D010586:Phagocytes / Q000187:drug effects* / Q000276:immunology*; D012160:Retina / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D016899:Interferon-beta
keywords: age‐related macular degeneration; choroidal neovascularization; interferon‐beta signaling; macrophages; microglia