Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy

Whitmore, S. Scott; Sohn, Elliott H.; Chirco, Kathleen R.; Drack, Arlene V.; Stone, Edwin M.; Tucker, Budd A.; Mullins, Robert F.

doi:10.1016/j.preteyeres.2014.11.005

Cited by 187 publications

(168 citation statements)

References 324 publications

(409 reference statements)

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“…[11][12][13][14][15] Cellular changes in advanced AMD include atrophy of the RPE, choriocapillaris and outer retina in nonexudative AMD, and the development of choroidal neovascularization in exudative AMD. [16][17][18] At the current time, any connection between ultrastructural changes observed in BM with age (mentioned above) and cellular changes that develop in AMD is not known. However, it is known that the structural changes that are due to aging within BM precede cellular changes in the RPE by one or two decades, well before there are signs of early AMD on clinical examination and imaging.…”

Section: Introductionmentioning

confidence: 99%

Reengineering Human Bruch's Membrane Increases Rod Outer Segment Phagocytosis by Human Retinal Pigment Epithelium

Moreira

Cai

Tezel

et al. 2015

Trans. Vis. Sci. Tech.

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Purpose: We have shown previously that Bruch's membrane (BM) aging decreases retinal pigment epithelium (RPE) phagocytosis. Herein, we determine the effects of BM reengineering on RPE phagocytosis.Methods: BM explants were dissected from young and old donor eyes. Some old BM explants were reengineered by cleaning with Triton X-100 and/or coating with extracellular matrix (ECM) ligands. ARPE-19 cell-derived ECM (ARPE-ECM) modified (''aged'') by sodium nitrite was subjected to similar treatments. ARPE-19 cells were then cultured to confluence onto the different surfaces. Fluorescently-labeled bovine rod outer segments (ROS) were fed to cells with or without aVb5 integrin antibody. Image acquisition and phagocytosis quantification was performed by fluorescence microscopy and ImageJ analysis.Results: Cleaning old donor-derived BM with detergent does not increase the uptake of ROS, but a combination of cleaning and coating with ECM ligands significantly increases RPE phagocytosis (54.9 6 6.2 vs. 83.5 6 6.5 arbitrary units; P , 0.05) to levels closer to young donor BM (123.6 6 9.9 arbitrary units). Similar effects were observed on nitrite-modified ARPE-ECM subjected to the same treatments. Incubation of aVb5 blocking antibody with ROS significantly decreased RPE phagocytosis. Conclusions:The detrimental effects of aging BM on RPE phagocytosis can be reversed by reengineering the BM surface with detergent cleaning and recoating with ECM ligands.Translation Relevance: These results demonstrate that the therapeutic success of transplanted RPE cells may require, at least in part, reengineering of diseased BM to make it a more suitable environment for attachment, survival and proper functioning of the RPE.

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Section: Introductionmentioning

confidence: 99%

Reengineering Human Bruch's Membrane Increases Rod Outer Segment Phagocytosis by Human Retinal Pigment Epithelium

Moreira

Cai

Tezel

et al. 2015

Trans. Vis. Sci. Tech.

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“…Immunostaining of human donor tissue shows that CD59 is predominantly found on the apical surface (16). Decreased CD59 expression (16) and increased MAC deposition in sub-RPE drusen and at the RPE-choroid interface (13,17) have been detected in AMD patient tissues, pointing to a breakdown in mechanisms that prevent MAC assembly. Activated complement components have also been detected in retinal tissue from the Abca4 −/− mouse model of Stargardt macular dystrophy, characterized by lipofuscin accumulation and accelerated formation of vitamin A dimers, such as A2E, in the RPE (7,8).…”

mentioning

confidence: 99%

Protective responses to sublytic complement in the retinal pigment epithelium

Tan

Toops

Lakkaraju

2016

Proc. Natl. Acad. Sci. U.S.A.

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The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration. Using polarized primary RPE and the pigmented Abca4 −/− Stargardt disease mouse model, we provide evidence for two protective responses occurring within minutes of complement attack, which are essential for maintaining mitochondrial health in the RPE. First, accelerated recycling of the membrane-bound complement regulator CD59 to the RPE cell surface inhibits MAC formation. Second, fusion of lysosomes with the RPE plasma membrane immediately after complement attack limits sustained elevations in intracellular calcium and prevents mitochondrial injury. Cholesterol accumulation in the RPE, induced by vitamin A dimers or oxidized LDL, inhibits these defense mechanisms by activating acid sphingomyelinase (ASMase), which increases tubulin acetylation and derails organelle traffic. Defective CD59 recycling and lysosome exocytosis after complement attack lead to mitochondrial fragmentation and oxidative stress in the RPE. Drugs that stimulate cholesterol efflux or inhibit ASMase restore both these critical safeguards in the RPE and avert complement-induced mitochondrial injury in vitro and in Abca4 −/− mice, indicating that they could be effective therapeutic approaches for macular degenerations.he complement system is an important regulator of immunity and inflammation. Complement activation by the classical, alternative, or lectin pathways results in the assembly of C5b-9 membrane attack complexes (MACs), which form membrane pores and cause target cell lysis. Within the eye, a low level of constant complement activity is necessary for immune surveillance, and several membrane-bound and soluble regulators prevent excessive complement activation (1). An imbalance between complement activation and inhibition in the retina is implicated in the pathogenesis of age-related macular degeneration (AMD), which causes central vision loss in more than 30 million people globally (reviewed in refs. 2-4).Evidence suggests that the retinal pigment epithelium (RPE), which helps maintain ocular immune privilege, is the first line of defense against unregulated complement activation in the retina (5). The complement cascade is activated by insults that disturb RPE homeostasis, including defective clearance of phagocytosed photoreceptor outer segments (6) and abnormal accumulation of vitamin A dimers (7-9) or oxidized lipids (10) in the RPE. Studies also show that exposure to sublytic levels of MAC alters RPE barrier integrity, causes...

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“…Cardinal features include accumulation of lipids and proteins within drusen and Bruch's membrane (6), RPE dysfunction/death, complementmediated attack and vaso-obliteration of the choriocapillaris (7), and photoreceptor atrophy ( Figure 1B). However, the precise etiology of AMD is unclear (7,8), and according to some experts it may be a spectrum of closely related diseases (9). Both genetic and environmental influences confer risk, but it is unclear which outer retinal components are affected first by the insult(s), and the order in which they are affected may differ between cases (8).…”

Section: Amdmentioning

confidence: 99%

“…First, the PI3/Akt/mTOR pathway has been shown to regulate RPE metabolism (21), and stimulation of the insulin/mTOR pathway in murine retinas significantly retards photoreceptor atrophy (22). Second, variants in complement cascade genes including CFH, CFI, CFB, and C3 are associated with AMD, and complement-mediated attacks on the choriocapillaris might be a primary event in AMD pathogenesis (7). Third, ECM receptor interactions are critical for choriocapillaris, Bruch's membrane, and RPE crosstalk (23).…”

Section: Nicotinamide Suppresses Signaling Cascades In Rpe That Mightmentioning

confidence: 99%

Nicotinamide: a novel treatment for age-related macular degeneration?

Westenskow

2017

Stem Cell Investig.

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Saini et al. recently reported in Cell StemCell that nicotinamide can suppress the expression of a broad set of genes in induced pluripotent stem cell-derived retinal pigment epithelium (iPS-RPE) cells that may contribute to age-related macular degeneration (AMD) (1). There are ample reasons to be excited about their findings, and many opportunities for future work. In this commentary, I will begin by providing background about the etiology of AMD before outlining some of the challenges of studying AMD using iPS-RPE. With that context in place, I will describe which elements of the Saini et al. study I find most exciting, and discuss potential future directions. The outer retina-a finely tuned machineThe outer half of the retina consists of hard working cells and structures that convert light into neural signals through phototransduction. Rod and cone photoreceptors initiate phototransduction when activated by light, but cannot complete the process without help from the multifunctional retinal pigment epithelium (RPE) or without fuel. Energy substrates for the RPE and photoreceptors are provided by a highly dense and fenestrated extraretinal vascular plexus, the choriocapillaris, which surrounds the outer retina ( Figure 1A).The choriocapillaris, RPE cells, and photoreceptors are all uniquely remarkable. According to many accounts, the blood flow rate and the vascular permeability of the choriocapillaris is higher than anywhere in the body (2).Oxygen and nutrients from the choriocapillaris are filtered and redistributed in the subretinal space through a pentalaminar matrix (Bruch's membrane) and by RPE cells. RPE also generate and secrete key vasculotrophic factors for choriocapillaris maintenance, deliver glucose to photoreceptors, recycle spent photopigments, absorb stray light, and phagocytose light damaged photoreceptor membranes to prevent oxidative stress (3). Photoreceptors can be activated by a single photon, and can respond appropriately to the wavelength and intensity of a light source. However, they are also extraordinarily metabolically demanding and inherently fragile (4). Maintaining the integrity and homeostasis of photoreceptors, RPE, and the choriocapillaris is imperative, and defects result in profound vision loss. Even finely tuned machines break down over timeThe prevalence of age-related vision loss should not be surprising considering the intense burdens placed on the choriocapillaris and RPE to support the remarkable metabolic demands of photoreceptors. In fact, AMD is a commonly occurring and leading cause of vision loss in industrialized countries. The global prevalence of AMD is steadily increasing and expected to reach epidemic proportions by the year 2040 when some experts estimate that 288 million people could be affected (5). To emphasize Editorial

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Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy

Cited by 187 publications

References 324 publications

Reengineering Human Bruch's Membrane Increases Rod Outer Segment Phagocytosis by Human Retinal Pigment Epithelium

Reengineering Human Bruch's Membrane Increases Rod Outer Segment Phagocytosis by Human Retinal Pigment Epithelium

Protective responses to sublytic complement in the retinal pigment epithelium

Nicotinamide: a novel treatment for age-related macular degeneration?

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