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Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration

BACKGROUND: Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1β (IL-1β) in modulating AMD-associated chemokines Ccl2, Cxc...

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Autores principales: Natoli, Riccardo, Fernando, Nilisha, Madigan, Michele, Chu-Tan, Joshua A., Valter, Krisztina, Provis, Jan, Rutar, Matt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404662/
https://www.ncbi.nlm.nih.gov/pubmed/28438165
http://dx.doi.org/10.1186/s13024-017-0175-y
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author Natoli, Riccardo
Fernando, Nilisha
Madigan, Michele
Chu-Tan, Joshua A.
Valter, Krisztina
Provis, Jan
Rutar, Matt
author_facet Natoli, Riccardo
Fernando, Nilisha
Madigan, Michele
Chu-Tan, Joshua A.
Valter, Krisztina
Provis, Jan
Rutar, Matt
author_sort Natoli, Riccardo
collection PubMed
description BACKGROUND: Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1β (IL-1β) in modulating AMD-associated chemokines Ccl2, Cxcl1, and Cxcl10 during photo-oxidative retinal damage, and the effect on both the accumulation of outer-retinal macrophages, and death of photoreceptors. METHODS: Inhibition of retinal IL-1β expression was performed using either siRNA or antibody neutralisation, which was intravitreally injected in SD rats prior to photo-oxidative damage. Changes in the expression and localisation of Il-1β, Ccl2, Cxcl1 and Cxcl10 genes were assessed using qPCR and in situ hybridisation, while the recruitment of retinal macrophages was detected using immunohistochemistry for IBA1. Levels of photoreceptor cell death were determined using TUNEL. RESULTS: Photo-oxidative damage elevated the expression of Il-1β and inflammasome-related genes, and IL-1β protein was detected in microglia infiltrating the outer retina. This was associated with increased expression of Ccl2, Cxcl1, and Cxcl10. Intravitreal IL-1β inhibitors suppressed chemokine expression following damage and reduced macrophage accumulation and photoreceptor death. Moreover, in Müller and RPE cell cultures, and in vivo, Ccl2, Cxcl1 and Cxcl10 were variously upregulated when stimulated with IL-1β, with increased macrophage accumulation detected in vivo. CONCLUSIONS: IL-1β is produced by retinal microglia and macrophages and promotes chemokine expression by Müller cells and RPE in retinal degeneration. Targeting IL-1β may prove efficacious in broadly suppressing chemokine-mediated inflammation in retinal dystrophies such as AMD.
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spelling pubmed-54046622017-04-27 Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration Natoli, Riccardo Fernando, Nilisha Madigan, Michele Chu-Tan, Joshua A. Valter, Krisztina Provis, Jan Rutar, Matt Mol Neurodegener Research Article BACKGROUND: Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1β (IL-1β) in modulating AMD-associated chemokines Ccl2, Cxcl1, and Cxcl10 during photo-oxidative retinal damage, and the effect on both the accumulation of outer-retinal macrophages, and death of photoreceptors. METHODS: Inhibition of retinal IL-1β expression was performed using either siRNA or antibody neutralisation, which was intravitreally injected in SD rats prior to photo-oxidative damage. Changes in the expression and localisation of Il-1β, Ccl2, Cxcl1 and Cxcl10 genes were assessed using qPCR and in situ hybridisation, while the recruitment of retinal macrophages was detected using immunohistochemistry for IBA1. Levels of photoreceptor cell death were determined using TUNEL. RESULTS: Photo-oxidative damage elevated the expression of Il-1β and inflammasome-related genes, and IL-1β protein was detected in microglia infiltrating the outer retina. This was associated with increased expression of Ccl2, Cxcl1, and Cxcl10. Intravitreal IL-1β inhibitors suppressed chemokine expression following damage and reduced macrophage accumulation and photoreceptor death. Moreover, in Müller and RPE cell cultures, and in vivo, Ccl2, Cxcl1 and Cxcl10 were variously upregulated when stimulated with IL-1β, with increased macrophage accumulation detected in vivo. CONCLUSIONS: IL-1β is produced by retinal microglia and macrophages and promotes chemokine expression by Müller cells and RPE in retinal degeneration. Targeting IL-1β may prove efficacious in broadly suppressing chemokine-mediated inflammation in retinal dystrophies such as AMD. BioMed Central 2017-04-24 /pmc/articles/PMC5404662/ /pubmed/28438165 http://dx.doi.org/10.1186/s13024-017-0175-y Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Natoli, Riccardo
Fernando, Nilisha
Madigan, Michele
Chu-Tan, Joshua A.
Valter, Krisztina
Provis, Jan
Rutar, Matt
Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration
title Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration
title_full Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration
title_fullStr Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration
title_full_unstemmed Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration
title_short Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration
title_sort microglia-derived il-1β promotes chemokine expression by müller cells and rpe in focal retinal degeneration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404662/
https://www.ncbi.nlm.nih.gov/pubmed/28438165
http://dx.doi.org/10.1186/s13024-017-0175-y
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