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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...

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Autores principales: Madeira, M. H., Rashid, K., Ambrósio, A. F., Santiago, A. R., Langmann, T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
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.
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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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