A model to study complement involvement in experimental retinal degeneration

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Abstract

Background

The complement system (CS) plays a role in the pathogenesis of a number of ocular diseases, including diabetic retinopathy (DR), glaucoma, uveitis, and age-related macular degeneration (AMD). Given that many of the complex eye-related degenerative diseases have limited treatment opportunities, we aimed to mimic the in vivo retinal degenerative process by developing a relevant co-culture system.

Method and materials

The adult porcine retina was co-cultured with the spontaneously arising human retinal pigment epithelial cells-19 (ARPE-19).

Results

Inflammatory activity was found after culture and included migrating microglial cells, gliosis, cell death, and CS activation (demonstrated by a minor increase in the secreted anaphylotoxin C3a in co-culture). CS components, including C1q, C3, C4, soluble C5b-9, and the C5a receptor, were expressed in the retina and/or ARPE cells after culture. C1q, C3, and CS regulators such as C4 binding protein (C4BP), factor H (CFH), and factor I (CFI) were secreted after culture.

Discussion

Thus, our research indicates that this co-culturing system may be useful for investigations of the CS and its involvement in experimental neurodegenerative diseases.

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Most cited references 83

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Drusen proteome analysis: an approach to the etiology of age-related macular degeneration.

John W. Crabb, Masaru Miyagi, Xiaorong GU … (2002)

Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch's membrane and are risk factors for developing age-related macular degeneration (AMD). The progression of AMD might be slowed or halted if the formation of drusen could be modulated. To work toward a molecular understanding of drusen formation, we have developed a method for isolating microgram quantities of drusen and Bruch's membrane for proteome analysis. Liquid chromatography tandem MS analyses of drusen preparations from 18 normal donors and five AMD donors identified 129 proteins. Immunocytochemical studies have thus far localized approximately 16% of these proteins in drusen. Tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin were the most common proteins observed in normal donor drusen whereas crystallin was detected more frequently in AMD donor drusen. Up to 65% of the proteins identified were found in drusen from both AMD and normal donors. However, oxidative protein modifications were also observed, including apparent crosslinked species of tissue metalloproteinase inhibitor 3 and vitronectin, and carboxyethyl pyrrole protein adducts. Carboxyethyl pyrrole adducts are uniquely generated from the oxidation of docosahexaenoate-containing lipids. By Western analysis they were found to be more abundant in AMD than in normal Bruch's membrane and were found associated with drusen proteins. Carboxymethyl lysine, another oxidative modification, was also detected in drusen. These data strongly support the hypothesis that oxidative injury contributes to the pathogenesis of AMD and suggest that oxidative protein modifications may have a critical role in drusen formation.

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The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.

Don H Anderson, Monte Radeke, Natasha Gallo … (2010)

During the past ten years, dramatic advances have been made in unraveling the biological bases of age-related macular degeneration (AMD), the most common cause of irreversible blindness in western populations. In that timeframe, two distinct lines of evidence emerged which implicated chronic local inflammation and activation of the complement cascade in AMD pathogenesis. First, a number of complement system proteins, complement activators, and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD. Subsequently, genetic studies revealed highly significant statistical associations between AMD and variants of several complement pathway-associated genes including: Complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3). In this article, we revisit our original hypothesis that chronic local inflammatory and immune-mediated events at the level of Bruch's membrane play critical roles in drusen biogenesis and, by extension, in the pathobiology of AMD. Secondly, we report the results of a new screening for additional AMD-associated polymorphisms in a battery of 63 complement-related genes. Third, we identify and characterize the local complement system in the RPE-choroid complex - thus adding a new dimension of biological complexity to the role of the complement system in ocular aging and AMD. Finally, we evaluate the most salient, recent evidence that bears directly on the role of complement in AMD pathogenesis and progression. Collectively, these recent findings strongly re-affirm the importance of the complement system in AMD. They lay the groundwork for further studies that may lead to the identification of a transcriptional disease signature of AMD, and hasten the development of new therapeutic approaches that will restore the complement-modulating activity that appears to be compromised in genetically susceptible individuals. Copyright 2009 Elsevier Ltd. All rights reserved.

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Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease.

R F Mullins, S R Russell, D. Anderson … (2000)

Age-related macular degeneration (AMD), a blinding disorder that compromises central vision, is characterized by the accumulation of extracellular deposits, termed drusen, between the retinal pigmented epithelium and the choroid. Recent studies in this laboratory revealed that vitronectin is a major component of drusen. Because vitronectin is also a constituent of abnormal deposits associated with a variety of diseases, drusen from human donor eyes were examined for compositional similarities with other extracellular disease deposits. Thirty-four antibodies to 29 different proteins or protein complexes were tested for immunoreactivity with hard and soft drusen phenotypes. These analyses provide a partial profile of the molecular composition of drusen. Serum amyloid P component, apolipoprotein E, immunoglobulin light chains, Factor X, and complement proteins (C5 and C5b-9 complex) were identified in all drusen phenotypes. Transcripts encoding some of these molecules were also found to be synthesized by the retina, retinal pigmented epithelium, and/or choroid. The compositional similarity between drusen and other disease deposits may be significant in view of the recently established correlation between AMD and atherosclerosis. This study suggests that similar pathways may be involved in the etiologies of AMD and other age-related diseases.

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Author and article information

Journal

Journal ID (nlm-ta): Ups J Med Sci

Journal ID (iso-abbrev): Ups. J. Med. Sci

Journal ID (publisher-id): IUPS

Title: Upsala Journal of Medical Sciences

Publisher: Taylor & Francis

ISSN (Print): 0300-9734

ISSN (Electronic): 2000-1967

Publication date (Print): March 2018

Publication date (Electronic): 13 February 2018

Volume: 123

Issue: 1

Pages: 28-42

Affiliations

[a ]Linnaeus University Faculty of Health and Life Science, Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden

[b ]Department of Clinical Neuroscience, Section for Ophthalmology and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden

[c ]Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden

[d ]School of Medical Sciences, Örebro University, Örebro, Sweden

Author notes

[*]

Equal contributors.

Supplemental data for this article can be accessed here .

CONTACT Camilla Mohlin Camilla.mohlin@ 123456lnu.se Linnaeus Center of Biomaterials Chemistry, Linnaeus University, 391 82 Kalmar, Sweden

Article

Publisher ID: iups-123-28

DOI: 10.1080/03009734.2018.1431744

PMC ID: 5901466

PubMed ID: 29436895

SO-VID: e9e630c0-c3c6-4c03-9262-9354dbbbc441

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 02 November 2017

Date revision received : 15 January 2018

Date accepted : 16 January 2018

Funding

This study was supported by grants from the Carmen and Bertil Regnérs Foundation, Crown Princess Margaretas Committee for the Blind, Olle Engqvist Foundation, Sven and Dagmar Saléns Foundation, Ögonfonden (‘The Eye Foundation’), FORSS (Medical Research Council of Southeast Sweden), the faculty of Medical Sciences at Örebro University, faculty grants from the Linnaeus University, and by the Swedish Medical Research Council (VR) grant.

A model to study complement involvement in experimental retinal degeneration

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Abstract

Background

Method and materials

Results

Discussion

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International Journal of Applied Technology in Medical Sciences

Most cited references 83

Drusen proteome analysis: an approach to the etiology of age-related macular degeneration.

The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.

Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease.

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