CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration

Abstract

The role of retinal microglial cells (MCs) in age-related macular degeneration (AMD) is unclear. Here we demonstrated that all retinal MCs express CX3C chemokine receptor 1 (CX3CR1) and that homozygosity for the CX3CR1 M280 allele, which is associated with impaired cell migration, increases the risk of AMD. In humans with AMD, MCs accumulated in the subretinal space at sites of retinal degeneration and choroidal neovascularization (CNV). In CX3CR1-deficient mice, MCs accumulated subretinally with age and albino background and after laser impact preceding retinal degeneration. Raising the albino mice in the dark prevented both events. The appearance of lipid-bloated subretinal MCs was drusen-like on funduscopy of senescent mice, and CX3CR1-dependent MC accumulation was associated with an exacerbation of experimental CNV. These results show that CX3CR1-dependent accumulation of subretinal MCs evokes cardinal features of AMD. These findings reveal what we believe to be a novel pathogenic process with important implications for the development of new therapies for AMD.

Interleukin-1β Inhibition Prevents Choroidal Neovascularization and Does Not Exacerbate Photoreceptor Degeneration

“…IL-1␤ significantly increases with age in Cx3cr1 Ϫ/Ϫ animals. This increase coincides with the observed subretinal inflammation in these animals 19 and might reflect IL-1␤ produced by subretinal inflammatory cells. In light-induced injury to BALB Cx3cr1 ϩ/ϩ and Cx3cr1 Ϫ/Ϫ mice, IL-1␤ was rapidly induced, similar to the rat and to laser-induced CNV.…”

“…Cx3cr1 Ϫ/Ϫ mice develop spontaneous subretinal macrophage accumulation that is associated with photoreceptor degeneration by the age of 18 months. 19 Similarly, these mice develop exaggerated photoreceptor degeneration in light-induced models. 20 We analyzed the expression and effect of IL-1␤ in the Cx3cr1 Ϫ/Ϫ model of AMD.…”

“…Furthermore, Cx3cr1 Ϫ/Ϫ mice develop spontaneous photoreceptor degeneration by the age of 18 months and exaggerated photoreceptor degeneration in light-induced models. 19,20 Here, we analyzed the expression and effect of IL-1␤ in the Cx3cr1 Ϫ/Ϫ model of AMD. First, we analyzed IL-1␤ expression in C57BL/6 Cx3cr1 ϩ/ϩ and C57BL/6 Cx3cr1 Ϫ/Ϫ mice at 3 and 18 months of age ( Figure 5A; n ϭ 4 eyes/group).…”

“…The increase of IL-1␤ protein levels in light-induced injury in BALB Cx3cr1 ϩ/ϩ and Cx3cr1 Ϫ/Ϫ mice was not different from each other and comparable to 18-month-old C57BL/6 Cx3cr1 Ϫ/Ϫ mice. To evaluate if IL-1␤ plays a role in photoreceptor degeneration in the context of CX3CR1 deficiency, we exposed 2-month-old BALB Cx3cr1 Ϫ/Ϫ mice before significant spontaneous degeneration was observed to light-induced degeneration 19 ( Figure 5C). PBS (n ϭ 4 mice) or IL-1Ra (n ϭ 6 mice) were injected subcutaneously at 1 mg/kg/d and intravitrealy (2 L of a 150-mg/mL solution) at day 1 and day 3 to ensure penetration of a possibly intact blood retinal barrier in the eye.…”

Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse

“…Furthermore, CX3CR1À/À microglia were shown to accumulate and promote retinal degeneration (Combadiere et al, 2007). In contrast, we observed significantly smaller ischemic damage/ neuronal apoptosis after MCAo in CX3CR1À/À mice than in mice having CX3CR1, suggesting that loss of CX3CR1 confers neuroprotection in ischemia.…”