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.
Highlights
Age-related macular degeneration (AMD) is the leading cause of visual impairment among the elderly, often resulting in blindness (Augood et al, 2006)
We first determined whether Ifnar1 signaling affects the three key events in laser-induced choroidal neovascularization (CNV), (i) microglia/macrophage activation, (ii) vascular leakage, and (iii) neovessel formation
To further define the cellular phenotype at the lesion sites, changes in their ramification and the length of processes were determined by counting the number of crossing points per individual cell using a grid image system (Chen et al, 2012). These observations revealed a significant reduction in grid cross points in Ifnar1À/À retinas compared to controls, which clearly indicates a general shift in the morphology of microglia and macrophages (Fig 1E)
Summary
Age-related macular degeneration (AMD) is the leading cause of visual impairment among the elderly, often resulting in blindness (Augood et al, 2006). It occurs in two main clinical forms, the dry form with geographic atrophy and the wet or exudative form. We have studied the role of IFN-b and its receptor Ifnar in the laser-induced choroidal neovascularization model mimicking age-related macular degeneration in mice (Lambert et al, 2013). We demonstrate a pivotal effect of Ifnar/IFN-b signaling in retinal microglia and macrophages cells that reduce the inflammatory and angiogenic events and thereby limit the development of CNV lesions
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