Interferon‐beta signaling in retinal mononuclear phagocytes attenuates pathological neovascularization

• Published in: EMBO molecular medicine 2016-06, Vol.8 (6), p.670-678
• Main Authors: Lückoff, Anika, Caramoy, Albert, Scholz, Rebecca, Prinz, Marco, Kalinke, Ulrich, Langmann, Thomas
• Format: Article
• Language: English
• Subjects: age‐related macular degeneration; Angiogenesis; Animals; Cell activation; choroidal neovascularization; Complement activation; Disease Models, Animal; EMBO19; EMBO27; EMBO46; Geriatrics; Homeostasis; Immune system; Immunology; Innate immunity; Interferon; Interferon-beta - metabolism; interferon‐beta signaling; Lasers; Lectins; Leukocytes (mononuclear); Macrophage Activation; Macrophages; Macular degeneration; Macular Degeneration - pathology; Medical imaging; Mice; Mice, Knockout; Microglia; Morphology; Neovascularization, Pathologic; Phagocytes; Phagocytes - drug effects; Phagocytes - immunology; Retina; Retina - pathology; Signal Transduction; Statistical analysis; Students; Tamoxifen; Vascularization
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201505994

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 Ifnar 1 −/− 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. Synopsis Innate immune activation is a hallmark of age‐related macular degeneration (AMD). Here, interferon‐beta signaling was identified as an intrinsic regulator of retinal mononuclear phagocytes and therefore as potential therapeutic target for AMD. Loss of Ifnar1 signaling triggers retinal microglia and macrophage reactivity and promotes angiogenesis in a laser‐induced model for AMD. Specific knockdown of Ifnar1 in mononuclear phagocytes affects their immunomodulatory potential and exacerbates choroidal neovascularization. IFN‐β therapy attenuates microgliosis and macrophage reactivity and thereby reduces choroidal neovascularization. Graphical Abstract Innate immune activation is a hallmark of age‐related macular degeneration (AMD). Here, interferon‐beta signaling was identified as an intrinsic regulator of retinal mononuclear phagocytes and therefore as potential therapeutic target for AMD.