Overstaying their welcome: defective CX3CR1 microglia eyed in macular degeneration

Abstract

Age-related macular degeneration (AMD), the most common cause of blindness in the elderly, is characterized by degeneration of the macula and can lead to loss of fine color vision. Alterations in inflammatory and immune system pathways, which arise from genetic differences, predispose individuals to AMD. Yet the mechanism of disease progression with respect to inflammation is not fully understood. In this issue of the JCI, the study by Combadière and colleagues shows that CX3C chemokine receptor 1-deficient (CX3CR1-deficient) mice have abnormal microglia that accumulate beneath the retina and contribute to the progression of AMD.

Figure 1. Loss of central vision in AMD patients.

(A) Representation of the visual field seen by a person with normal vision and by an AMD patient with a loss of central color vision. (B) Schematic of a normal human eye compared with an AMD eye depicting deposits of drusen (yellow spots) and choroidal neovascularization with subretinal hemorrhage in the macula (red). (C) Schematic cross-section of a normal eye through the macula shows retinal neuronal layers, RPE, Bruch’s membrane, and choroid vessels. In AMD, the intimate relation among photoreceptors, RPE, and choroid is disrupted by drusen (lipid and cellular debris–containing deposits). The formation of drusen separates RPE from Bruch’s membrane and the underlying choroidal vessels in association with RPE atrophy and photoreceptor degeneration (hallmarks of dry AMD). In wet AMD with choroidal neovascularization, abnormal leaky choroidal vessels proliferate and penetrate the altered Bruch’s membrane protruding into the subretinal space, causing hemorrhage and rapid loss of vision.

Figure 2. Proposed role of CX3CR1 and microglia in AMD.

(A) In the normal retina, rod and cone photoreceptor outer segments are composed of thousands of photopigment-containing membrane discs that are continuously shed from the tips of the cells and recycled. The discarded discs are removed by RPE phagocytosis and reprocessed. (B) Additionally, microglia expressing CX3CR1 phagocytize cellular debris caused by daily insults (such as aging and cellular stress) and help maintain a healthy eye. (C) AMD resulting from loss of CX3CR1 expression is initiated by the same daily insults. However, as reported by Combadière et al. (6), when microglia lacking CX3CR1 are recruited to the area of damage they remain there, in part because of abnormal migration. CX3CR1-deficient microglia are proinflammatory (versus antiinflammatory CX3CR1-replete microglia; ref. 16) and recruit other proinflammatory cells. This response exacerbates the cellular damage that occurs with normal degeneration. (D) The increased accumulation of proinflammatory, CX3CR1-negative (16) microglia in the subretinal space appears to add to the formation of drusen (6), which contribute to loss of RPE function and photoreceptor degeneration (dry AMD). (E) Finally, as drusen build up and separate the RPE from the choroidal vasculature, the resulting hypoxia triggers proangiogenic signals, which foster choroidal neovascularization (wet AMD).