Abstract
Background: CD36, a member of the class B scavenger receptor family, participates in Toll-like receptor signaling on mononuclear phagocytes (MP) and can promote sterile pathogenic inflammation. We here analyzed the effect of CD36 deficiency on retinal inflammation and photoreceptor degeneration, the hallmarks of age-related macular degeneration (AMD), that characterize Cx3cr1−/−mice.Methods: We analyzed subretinal MP accumulation, and cone- and rod-degeneration in light-challenged and aged, CD36 competent or deficient, hyper-inflammatory Cx3cr1−/− mice, using histology and immune-stained retinal flatmounts. Monocytes (Mo) were subretinally adoptively transferred to evaluate their elimination rate from the subretinal space and Interleukin 6 (IL-6) secretion from cultured Mo-derived cells (MdCs) of the different mouse strains were analyzed.Results: CD36 deficient Cx3cr1−/− mice were protected against age- and light-induced subretinal inflammation and associated cone and rod degeneration. CD36 deficiency in Cx3cr1−/− MPs inhibited their prolonged survival in the immune-suppressive subretinal space and reduced the exaggerated IL-6 secretion observed in Cx3cr1−/− MPs that we previously showed leads to increased subretinal MP survival.Conclusion: Cd36 deficiency significantly protected hyperinflammatory Cx3cr1−/− mice against subretinal MP accumulation and associated photoreceptor degeneration. The observed CD36-dependent induction of pro-inflammatory IL-6 might be at least partially responsible for the prolonged MP survival in the immune-suppressive environment and its pathological consequences on photoreceptor homeostasis.
Highlights
While mononuclear phagocytes (MP) accumulation observed around large drusen in early Age-related Macular Degeneration (AMD) [4, 6] might control debris accumulation, we showed that macrophages/dendritic cells (MdC) invariably participate in the infiltrate in and around GA lesions [6], where they are closely associated with rod and cone degeneration [3]
We evaluated whether Cd36 deficiency influenced the rod and cone degeneration that is associated with MP accumulation in Cx3cr1−/− mice [5, 6, 29]
Micrographs revealed that Cx3cr1−/−Cd36−/− mice were protected against the thinning of the outer nuclear layer that hosts the photoreceptor nuclei, which is observed in aged Cx3cr1-deficient mice [6] (Figure 2A)
Summary
Age-related Macular Degeneration (AMD) is a common [1], highly heritable, neuroinflammatory disorder characterized by central, sizeable deposits under the retinal pigment epithelium (drusen) in its early form and choroidal neovascularisation (CNV, wet AMD) or an extending lesion of the outer central retina (geographic atrophy) in its late form [2].We [3,4,5,6] and others [7, 8] showed that both advanced forms [wet AMD [5] and Geographic Atrophy, GA [3, 4, 6]] are associated with non-resolving accumulation of mononuclear phagocytes (MP) in the subretinal space. The subretinal space does not contain blood- and lymphatic-vessels, and is devoid of immune cells, including resident MCs [4, 5, 7, 8, 10]. Among others this particularity is due to the potent immunosuppressive, pro-apoptotic factors produced by the RPE that eliminate infiltrating leukocytes [4, 11]. We here analyzed the effect of CD36 deficiency on retinal inflammation and photoreceptor degeneration, the hallmarks of age-related macular degeneration (AMD), that characterize Cx3cr1−/−mice
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