Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration

Lueck, Katharina; Wasmuth, Susanne; Williams, Jennifer A. E.; Hughes, Timothy R.; Morgan, B. Paul; Lommatzsch, Albrecht; Greenwood, John; Moss, Sarah E.; Pauleikhoff, Daniel

doi:10.1038/eye.2011.109

Cited by 70 publications

(54 citation statements)

References 48 publications

(45 reference statements)

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“…Both appear to involve chronic inflammation of the RPE through sublethal deposition of the MAC (49). In Abca4 Ϫ/Ϫ mice and STGD1 patients, complement attack on RPE cells is stimulated by bisretinoid accumulation and subsequent oxidation.…”

Section: Discussionmentioning

confidence: 99%

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

Radu

Jiang

et al. 2014

Journal of Biological Chemistry

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Background: AMD and STGD1 are blinding diseases with similar clinical presentations but unrelated genetic causes. Results: Bisretinoid-dependent complement reactivity on RPE cells involves the alternative pathway and depends on the CFH haplotype. Conclusion: Inefficient CFH synthesis because of either Y402H and I62V substitutions or bisretinoid accumulation predisposes RPE cells to disease. Significance: These results suggest a common inflammatory etiology for AMD and STGD1.

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Section: Discussionmentioning

confidence: 99%

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

Radu

Jiang

et al. 2014

Journal of Biological Chemistry

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“…These proteins can deposit on the plasma membrane of RPE cells to create a sublytic complex that degrades RPE function without killing the cell (45,46). CD46 is expressed in the basolateral membranes of human RPE cells, where it is exposed to the choroidal circulation.…”

Section: Accumulation Of Bisretinoid Pigments In the Rpe Of Abca4mentioning

confidence: 99%

Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease

Lenis

Sarfare

Jiang

et al. 2017

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

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Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4−/− (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice. CRPs prevent attack on host cells by the complement system, and complement receptor 1-like protein y (CRRY) is an important CRP in mice. Here we attempted to rescue the phenotype in STGD1 mice by increasing expression of CRRY in the RPE using a gene therapy approach. We injected recombinant adeno-associated virus containing the CRRY coding sequence (AAV-CRRY) into the subretinal space of 4-wk-old Abca4 −/− mice. This resulted in sustained, several-fold increased expression of CRRY in the RPE, which significantly reduced the complement factors C3/C3b in the RPE. Unexpectedly, AAV-CRRYtreated STGD1 mice also showed reduced accumulation of bisretinoids compared with sham-injected STGD1 control mice. Furthermore, we observed slower photoreceptor degeneration and increased visual chromophore in 1-y-old AAV-CRRY-treated STGD1 mice. Rescue of the STGD1 phenotype by AAV-CRRY gene therapy suggests that complement attack on the RPE is an important etiologic factor in STGD1. Modulation of the complement system by locally increasing CRP expression using targeted gene therapy represents a potential treatment strategy for STGD1 and other retinopathies associated with complement dysregulation.recessive Stargardt macular degeneration | complement system | retinal pigment epithelium | bisretinoids | gene therapy R ecessive Stargardt macular degeneration (STGD1) is a blinding disease of children and young adults caused by mutations in the ATP binding cassette subfamily A member 4 (ABCA4) gene (1, 2). The pathological hallmark of STGD1 is deposition of autofluorescent lipofuscin in the retinal pigment epithelium (RPE), which precedes photoreceptor degeneration (3, 4). The exact mechanism of how RPE lipofuscin accumulation disrupts overall RPE performance is poorly understood. The RPE fulfills several photoreceptor support tasks, including phagocytosis of distal outer segments (OS) and processing of visual retinoids (5-8). In addition, the RPE plays a major role in controlling the ocular immune response through expression of various complement negative regulatory proteins (CRPs) (9). For these reasons, photoreceptors are critically dependent on a healthy RPE for continued viability.The ABCA4 transporter clears retinaldehyde released by photobleached rhodopsin and cone-opsins from OS discs in the form of N-retinylidene phosphatidylethanolamine (N-ret-PE) (10). As a result, mice lacking ABCA4 accumulate retinaldehyde and N-ret-PE in their OS after light exposu...

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“…This molecule is the most important surface-bound negative regulator of complement activation on RPE cells [23]. In our previous study an enhanced cytokine production by RPE cells was found by a protocol using an antiserum targeting CD59 before the addition of human complement serum (HCS) [24]. …”

Section: Introductionmentioning

confidence: 99%

Complement Stimulates Retinal Pigment Epithelial Cells to Undergo Pro-Inflammatory Changes

Lueck

Busch²,

Moss³

et al. 2015

Ophthalmic Res

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Background/Aims: We examined the effect of human complement sera (HCS) on retinal pigment epithelial (RPE) cells with respect to pro-inflammatory mediators relevant in early age-related macular degeneration (AMD). Methods: RPE cells were treated with complement-containing HCS or with heat-inactivated (HI) HCS or C7-deficient HCS as controls. Cells were analysed for C5b-9 using immunocytochemistry and flow cytometry. Interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) were quantified by ELISA and RT-PCR. Tumour necrosis factor-a (TNF-a), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), were analysed by Western blotting. The intracellular distribution of nuclear factor (NF)-κB was investigated by immunofluorescence. Results: A concentration-dependent increased staining for C5b-9 but no influence on cell viability was observed after HCS treatment. ELISA and RT-PCR analysis revealed elevated secretion and expression of IL-6, IL-8, and MCP-1. Western blot analysis showed a concentration-dependent increase in ICAM-1, VCAM-1, and TNF-a in response to HCS, and immunofluorescence staining revealed nuclear translocation of NF-κB. Conclusion: This study suggests that complement stimulates NF-κB activation in RPE cells that might further create a pro-inflammatory environment. All these factors together may support early AMD development.

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Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration

Cited by 70 publications

References 48 publications

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease

Complement Stimulates Retinal Pigment Epithelial Cells to Undergo Pro-Inflammatory Changes

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