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Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro
Age-related macular degeneration (AMD) is characterized by pathological changes in the retinal pigment epithelium (RPE) and loss of photoreceptors. Growing evidence has demonstrated that reactive microglial cells trigger RPE dysfunction and loss of photoreceptors, and inflammasome pathways and compl...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797099/ https://www.ncbi.nlm.nih.gov/pubmed/29396515 http://dx.doi.org/10.1038/s41598-018-20733-2 |
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author | Madeira, M. H. Rashid, K. Ambrósio, A. F. Santiago, A. R. Langmann, T. |
author_facet | Madeira, M. H. Rashid, K. Ambrósio, A. F. Santiago, A. R. Langmann, T. |
author_sort | Madeira, M. H. |
collection | PubMed |
description | Age-related macular degeneration (AMD) is characterized by pathological changes in the retinal pigment epithelium (RPE) and loss of photoreceptors. Growing evidence has demonstrated that reactive microglial cells trigger RPE dysfunction and loss of photoreceptors, and inflammasome pathways and complement activation contribute to AMD pathogenesis. We and others have previously shown that adenosine A(2A) receptor (A(2A)R) blockade prevents microglia-mediated neuroinflammatory processes and mediates protection to the retina. However, it is still unknown whether blocking A(2A)R in microglia protects against the pathological features of AMD. Herein, we show that an A(2A)R antagonist, SCH58261, prevents the upregulation of the expression of pro-inflammatory mediators and the alterations in the complement system triggered by an inflammatory challenge in human microglial cells. Furthermore, blockade of A(2A)R in microglia decreases the inflammatory response, as well as complement and inflammasome activation, in ARPE-19 cells exposed to conditioned medium of activated microglia. Finally, we also show that blocking A(2A)R in human microglia increases the clearance of apoptotic photoreceptors. This study opens the possibility of using selective A(2A)R antagonists in therapy for AMD, by modulating the interplay between microglia, RPE and photoreceptors. |
format | Online Article Text |
id | pubmed-5797099 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57970992018-02-12 Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro Madeira, M. H. Rashid, K. Ambrósio, A. F. Santiago, A. R. Langmann, T. Sci Rep Article Age-related macular degeneration (AMD) is characterized by pathological changes in the retinal pigment epithelium (RPE) and loss of photoreceptors. Growing evidence has demonstrated that reactive microglial cells trigger RPE dysfunction and loss of photoreceptors, and inflammasome pathways and complement activation contribute to AMD pathogenesis. We and others have previously shown that adenosine A(2A) receptor (A(2A)R) blockade prevents microglia-mediated neuroinflammatory processes and mediates protection to the retina. However, it is still unknown whether blocking A(2A)R in microglia protects against the pathological features of AMD. Herein, we show that an A(2A)R antagonist, SCH58261, prevents the upregulation of the expression of pro-inflammatory mediators and the alterations in the complement system triggered by an inflammatory challenge in human microglial cells. Furthermore, blockade of A(2A)R in microglia decreases the inflammatory response, as well as complement and inflammasome activation, in ARPE-19 cells exposed to conditioned medium of activated microglia. Finally, we also show that blocking A(2A)R in human microglia increases the clearance of apoptotic photoreceptors. This study opens the possibility of using selective A(2A)R antagonists in therapy for AMD, by modulating the interplay between microglia, RPE and photoreceptors. Nature Publishing Group UK 2018-02-02 /pmc/articles/PMC5797099/ /pubmed/29396515 http://dx.doi.org/10.1038/s41598-018-20733-2 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Madeira, M. H. Rashid, K. Ambrósio, A. F. Santiago, A. R. Langmann, T. Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro |
title | Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro |
title_full | Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro |
title_fullStr | Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro |
title_full_unstemmed | Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro |
title_short | Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro |
title_sort | blockade of microglial adenosine a2a receptor impacts inflammatory mechanisms, reduces arpe-19 cell dysfunction and prevents photoreceptor loss in vitro |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797099/ https://www.ncbi.nlm.nih.gov/pubmed/29396515 http://dx.doi.org/10.1038/s41598-018-20733-2 |
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