The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration
Although the statement that age is the greatest risk factor for Age-related macular degeneration (AMD) is widely accepted, the cellular and molecular explanations for that clinical statement are not generally known. A major focus of AMD research is the retinal pigment epithelium (RPE)/choroid. The p...
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| description | Although the statement that age is the greatest risk factor for Age-related macular degeneration (AMD) is widely accepted, the cellular and molecular explanations for that clinical statement are not generally known. A major focus of AMD research is the retinal pigment epithelium (RPE)/choroid. The purpose of this study was to characterize the changes in the RPE/choroid with age that may provide a background for the development of AMD.
We compared the transcriptional profiles, key protein levels and histology of the RPE/choroid from young and old mice. Using three statistical methods, microarray data demonstrated marked changes in the old mouse. There were 315 genes differentially expressed with age; most of these genes were related to immune responses and inflammatory activity. Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling. By contrast, the adjacent neural retina showed completely different age-related changes. The levels of proteins that participate in leukocyte extravasation and complement pathways were consistently increased in the normal, aged RPE/choroid. Furthermore, there was increased gene expression and protein levels of leukocyte attracting signal, chemokine ligand 2 (Ccl2) in aged RPE/choroid. In old animals, there was marked extravasation and accumulation of leukocytes from the choroidal circulation onto Bruch's membrane and into the RPE.
These phenotypic changes indicate that the RPE/choroid in the normal, old mouse has become an immunologically active tissue. There are signals from the normal, aged RPE/choroid which recruit leukocytes from the circulation and activate the complement cascade. These age-related changes that occur in the RPE/choroid with age, to the extent that they occur in the human retina, may provide the background for an error in regulation of immunological activity to cause AMD to appear in an elderly individual. |
| doi_str_mv | 10.1371/journal.pone.0002339 |
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We compared the transcriptional profiles, key protein levels and histology of the RPE/choroid from young and old mice. Using three statistical methods, microarray data demonstrated marked changes in the old mouse. There were 315 genes differentially expressed with age; most of these genes were related to immune responses and inflammatory activity. Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling. By contrast, the adjacent neural retina showed completely different age-related changes. The levels of proteins that participate in leukocyte extravasation and complement pathways were consistently increased in the normal, aged RPE/choroid. Furthermore, there was increased gene expression and protein levels of leukocyte attracting signal, chemokine ligand 2 (Ccl2) in aged RPE/choroid. In old animals, there was marked extravasation and accumulation of leukocytes from the choroidal circulation onto Bruch's membrane and into the RPE.
These phenotypic changes indicate that the RPE/choroid in the normal, old mouse has become an immunologically active tissue. There are signals from the normal, aged RPE/choroid which recruit leukocytes from the circulation and activate the complement cascade. These age-related changes that occur in the RPE/choroid with age, to the extent that they occur in the human retina, may provide the background for an error in regulation of immunological activity to cause AMD to appear in an elderly individual.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0002339</identifier><identifier>PMID: 18523633</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Age ; Age related diseases ; Aging ; Aging - pathology ; Algorithms ; Animals ; Bayesian analysis ; Bioinformatics ; Biomarkers ; Cascades ; Choroid - pathology ; Comparative analysis ; Complement ; Complement Activation ; Cytokines ; Disease ; DNA microarrays ; Epithelium ; Extravasation ; Gene expression ; Gene Expression Profiling ; Genes ; Genomes ; Geriatrics ; Histology ; Immune response ; Immunology ; Inflammation ; Interleukin 10 ; Killer cells ; Laboratories ; Leukocytes ; Macular degeneration ; Macular Degeneration - pathology ; Male ; Medicine ; Mice ; Mice, Inbred C57BL ; Monocyte chemoattractant protein 1 ; Natural killer cells ; Older people ; Ophthalmology ; Ophthalmology/Macular Disorders ; Ophthalmology/Retinal Disorders ; Pathogenesis ; Photoreceptors ; Physiological aspects ; Pigment Epithelium of Eye - pathology ; Proteins ; Retina ; Retinal pigment epithelium ; Reverse Transcriptase Polymerase Chain Reaction ; Risk factors ; Signal transduction ; Statistical methods ; Transcription ; Transcription, Genetic ; Up-Regulation</subject><ispartof>PloS one, 2008-06, Vol.3 (6), p.e2339-e2339</ispartof><rights>COPYRIGHT 2008 Public Library of Science</rights><rights>2008 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Chen et al. 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c759t-775f85b5b99b5172861769bc447370038d9668f1d518012374e704928e496d1e3</citedby><cites>FETCH-LOGICAL-c759t-775f85b5b99b5172861769bc447370038d9668f1d518012374e704928e496d1e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394659/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394659/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18523633$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Koch, Karl-Wilhelm</contributor><creatorcontrib>Chen, Huiyi</creatorcontrib><creatorcontrib>Liu, Bin</creatorcontrib><creatorcontrib>Lukas, Thomas J</creatorcontrib><creatorcontrib>Neufeld, Arthur H</creatorcontrib><title>The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Although the statement that age is the greatest risk factor for Age-related macular degeneration (AMD) is widely accepted, the cellular and molecular explanations for that clinical statement are not generally known. A major focus of AMD research is the retinal pigment epithelium (RPE)/choroid. The purpose of this study was to characterize the changes in the RPE/choroid with age that may provide a background for the development of AMD.
We compared the transcriptional profiles, key protein levels and histology of the RPE/choroid from young and old mice. Using three statistical methods, microarray data demonstrated marked changes in the old mouse. There were 315 genes differentially expressed with age; most of these genes were related to immune responses and inflammatory activity. Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling. By contrast, the adjacent neural retina showed completely different age-related changes. The levels of proteins that participate in leukocyte extravasation and complement pathways were consistently increased in the normal, aged RPE/choroid. Furthermore, there was increased gene expression and protein levels of leukocyte attracting signal, chemokine ligand 2 (Ccl2) in aged RPE/choroid. In old animals, there was marked extravasation and accumulation of leukocytes from the choroidal circulation onto Bruch's membrane and into the RPE.
These phenotypic changes indicate that the RPE/choroid in the normal, old mouse has become an immunologically active tissue. There are signals from the normal, aged RPE/choroid which recruit leukocytes from the circulation and activate the complement cascade. These age-related changes that occur in the RPE/choroid with age, to the extent that they occur in the human retina, may provide the background for an error in regulation of immunological activity to cause AMD to appear in an elderly individual.</description><subject>Age</subject><subject>Age related diseases</subject><subject>Aging</subject><subject>Aging - pathology</subject><subject>Algorithms</subject><subject>Animals</subject><subject>Bayesian analysis</subject><subject>Bioinformatics</subject><subject>Biomarkers</subject><subject>Cascades</subject><subject>Choroid - pathology</subject><subject>Comparative analysis</subject><subject>Complement</subject><subject>Complement Activation</subject><subject>Cytokines</subject><subject>Disease</subject><subject>DNA microarrays</subject><subject>Epithelium</subject><subject>Extravasation</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Genes</subject><subject>Genomes</subject><subject>Geriatrics</subject><subject>Histology</subject><subject>Immune response</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Interleukin 10</subject><subject>Killer cells</subject><subject>Laboratories</subject><subject>Leukocytes</subject><subject>Macular degeneration</subject><subject>Macular Degeneration - pathology</subject><subject>Male</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Monocyte chemoattractant protein 1</subject><subject>Natural killer cells</subject><subject>Older people</subject><subject>Ophthalmology</subject><subject>Ophthalmology/Macular Disorders</subject><subject>Ophthalmology/Retinal Disorders</subject><subject>Pathogenesis</subject><subject>Photoreceptors</subject><subject>Physiological aspects</subject><subject>Pigment Epithelium of Eye - pathology</subject><subject>Proteins</subject><subject>Retina</subject><subject>Retinal pigment epithelium</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Risk factors</subject><subject>Signal transduction</subject><subject>Statistical methods</subject><subject>Transcription</subject><subject>Transcription, Genetic</subject><subject>Up-Regulation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7rr6D0QLwoIXM5s0bT68EJbFj4GFBV29DWl62mZIm5qkouCPN3VGnRFBCSQhec6b5M05WfYYozUmDF9s3exHZdeTG2GNECoIEXeyUyxIsaIFIncP5ifZgxC2CFWEU3o_O8G8Kggl5DT7dttDrjpocg_RJL18Mt0AY8xhMrEHa-bhQvfOO9O8yFU-uZg2TeLCXIfoVZyHvHU-T2w-qdi7DkYIJuSuXXRXHqyKSX5QerbK5w0sQIozbnyY3WuVDfBoP55lH16_ur16u7q-ebO5urxeaVaJuGKsanlVV7UQdYVZwSlmVNS6LBlhCBHeCEp5i5sKc4QLwkpgqBQFh1LQBgM5y57udCfrgtwbFyQmuCg455gnYrMjGqe2cvJmUP6rdMrIHwvOd1L5aLQFWetW1VwTQaukD5qzmtWoosl_LVijktbL_WlzPUCjk19e2SPR453R9LJzn2VBREkrkQTO9wLefZohRDmYoMFaNYKbg2SYpgRI3b_AAiMiGC4T-OwP8O8mrHdUp9I7zdi6dD2dWgOD0SnNWpPWL0tW0JILtFz0-VFAYiJ8iZ2aQ5Cb9-_-n735eMyeH7A9KBv74Oy85Ew4BssdqL0LwUP7y2WM5FIlP98plyqR-ypJYU8Of-h30L4syHcm6A4q</recordid><startdate>20080604</startdate><enddate>20080604</enddate><creator>Chen, Huiyi</creator><creator>Liu, Bin</creator><creator>Lukas, Thomas J</creator><creator>Neufeld, Arthur H</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7TK</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20080604</creationdate><title>The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration</title><author>Chen, Huiyi ; Liu, Bin ; Lukas, Thomas J ; Neufeld, Arthur H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c759t-775f85b5b99b5172861769bc447370038d9668f1d518012374e704928e496d1e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Age</topic><topic>Age related diseases</topic><topic>Aging</topic><topic>Aging - pathology</topic><topic>Algorithms</topic><topic>Animals</topic><topic>Bayesian analysis</topic><topic>Bioinformatics</topic><topic>Biomarkers</topic><topic>Cascades</topic><topic>Choroid - pathology</topic><topic>Comparative analysis</topic><topic>Complement</topic><topic>Complement Activation</topic><topic>Cytokines</topic><topic>Disease</topic><topic>DNA microarrays</topic><topic>Epithelium</topic><topic>Extravasation</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Genes</topic><topic>Genomes</topic><topic>Geriatrics</topic><topic>Histology</topic><topic>Immune response</topic><topic>Immunology</topic><topic>Inflammation</topic><topic>Interleukin 10</topic><topic>Killer cells</topic><topic>Laboratories</topic><topic>Leukocytes</topic><topic>Macular degeneration</topic><topic>Macular Degeneration - pathology</topic><topic>Male</topic><topic>Medicine</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Monocyte chemoattractant protein 1</topic><topic>Natural killer cells</topic><topic>Older people</topic><topic>Ophthalmology</topic><topic>Ophthalmology/Macular Disorders</topic><topic>Ophthalmology/Retinal Disorders</topic><topic>Pathogenesis</topic><topic>Photoreceptors</topic><topic>Physiological aspects</topic><topic>Pigment Epithelium of Eye - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Huiyi</au><au>Liu, Bin</au><au>Lukas, Thomas J</au><au>Neufeld, Arthur H</au><au>Koch, Karl-Wilhelm</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2008-06-04</date><risdate>2008</risdate><volume>3</volume><issue>6</issue><spage>e2339</spage><epage>e2339</epage><pages>e2339-e2339</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Although the statement that age is the greatest risk factor for Age-related macular degeneration (AMD) is widely accepted, the cellular and molecular explanations for that clinical statement are not generally known. A major focus of AMD research is the retinal pigment epithelium (RPE)/choroid. The purpose of this study was to characterize the changes in the RPE/choroid with age that may provide a background for the development of AMD.
We compared the transcriptional profiles, key protein levels and histology of the RPE/choroid from young and old mice. Using three statistical methods, microarray data demonstrated marked changes in the old mouse. There were 315 genes differentially expressed with age; most of these genes were related to immune responses and inflammatory activity. Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling. By contrast, the adjacent neural retina showed completely different age-related changes. The levels of proteins that participate in leukocyte extravasation and complement pathways were consistently increased in the normal, aged RPE/choroid. Furthermore, there was increased gene expression and protein levels of leukocyte attracting signal, chemokine ligand 2 (Ccl2) in aged RPE/choroid. In old animals, there was marked extravasation and accumulation of leukocytes from the choroidal circulation onto Bruch's membrane and into the RPE.
These phenotypic changes indicate that the RPE/choroid in the normal, old mouse has become an immunologically active tissue. There are signals from the normal, aged RPE/choroid which recruit leukocytes from the circulation and activate the complement cascade. These age-related changes that occur in the RPE/choroid with age, to the extent that they occur in the human retina, may provide the background for an error in regulation of immunological activity to cause AMD to appear in an elderly individual.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>18523633</pmid><doi>10.1371/journal.pone.0002339</doi><tpages>e2339</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Age Age related diseases Aging Aging - pathology Algorithms Animals Bayesian analysis Bioinformatics Biomarkers Cascades Choroid - pathology Comparative analysis Complement Complement Activation Cytokines Disease DNA microarrays Epithelium Extravasation Gene expression Gene Expression Profiling Genes Genomes Geriatrics Histology Immune response Immunology Inflammation Interleukin 10 Killer cells Laboratories Leukocytes Macular degeneration Macular Degeneration - pathology Male Medicine Mice Mice, Inbred C57BL Monocyte chemoattractant protein 1 Natural killer cells Older people Ophthalmology Ophthalmology/Macular Disorders Ophthalmology/Retinal Disorders Pathogenesis Photoreceptors Physiological aspects Pigment Epithelium of Eye - pathology Proteins Retina Retinal pigment epithelium Reverse Transcriptase Polymerase Chain Reaction Risk factors Signal transduction Statistical methods Transcription Transcription, Genetic Up-Regulation |
| title | The aged retinal pigment epithelium/choroid: a potential substratum for the pathogenesis of age-related macular degeneration |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-04T03%3A23%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20aged%20retinal%20pigment%20epithelium/choroid:%20a%20potential%20substratum%20for%20the%20pathogenesis%20of%20age-related%20macular%20degeneration&rft.jtitle=PloS%20one&rft.au=Chen,%20Huiyi&rft.date=2008-06-04&rft.volume=3&rft.issue=6&rft.spage=e2339&rft.epage=e2339&rft.pages=e2339-e2339&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0002339&rft_dat=%3Cgale_plos_%3EA472648909%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1312288818&rft_id=info:pmid/18523633&rft_galeid=A472648909&rft_doaj_id=oai_doaj_org_article_bcfab8c3965e49ec87b7b056233c97da&rfr_iscdi=true |