Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice

Abstract The complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the...

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Autores principales:	Donita L. Garland, Eric A. Pierce, Rosario Fernandez-Godino
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2259019cd6ae4e0484dfbf83b812201a
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spelling	oai:doaj.org-article:2259019cd6ae4e0484dfbf83b812201a2021-12-02T15:52:26ZComplement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice10.1038/s41598-021-89978-82045-2322https://doaj.org/article/2259019cd6ae4e0484dfbf83b812201a2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89978-8https://doaj.org/toc/2045-2322Abstract The complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the development of efficient therapies to reduce or stop disease progression. We have previously demonstrated that C3 blockage prevents the formation of sub-RPE deposits in a mouse model of EFEMP1-associated macular degeneration. In this study, we have used double mutant Efemp1 R345W/R345W:C5 -/- mice to investigate the role of C5 in the formation of sub-RPE deposits in vivo and in vitro. The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits. Contrarily, the absence of C5 in RPE cultures promotes complement dysregulation that results in increased activation of C3, which likely contributes to deposit formation even in the absence of EFEMP1-R345W mutant protein. The results also suggest that genetic ablation of C5 alters the extracellular matrix turnover through an effect on matrix metalloproteinases in RPE cell cultures. These results confirm that C3 rather than C5 could be an effective therapeutic target to treat early AMD.Donita L. GarlandEric A. PierceRosario Fernandez-GodinoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Donita L. Garland Eric A. Pierce Rosario Fernandez-Godino Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice
description	Abstract The complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the development of efficient therapies to reduce or stop disease progression. We have previously demonstrated that C3 blockage prevents the formation of sub-RPE deposits in a mouse model of EFEMP1-associated macular degeneration. In this study, we have used double mutant Efemp1 R345W/R345W:C5 -/- mice to investigate the role of C5 in the formation of sub-RPE deposits in vivo and in vitro. The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits. Contrarily, the absence of C5 in RPE cultures promotes complement dysregulation that results in increased activation of C3, which likely contributes to deposit formation even in the absence of EFEMP1-R345W mutant protein. The results also suggest that genetic ablation of C5 alters the extracellular matrix turnover through an effect on matrix metalloproteinases in RPE cell cultures. These results confirm that C3 rather than C5 could be an effective therapeutic target to treat early AMD.
format	article
author	Donita L. Garland Eric A. Pierce Rosario Fernandez-Godino
author_facet	Donita L. Garland Eric A. Pierce Rosario Fernandez-Godino
author_sort	Donita L. Garland
title	Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice
title_short	Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice
title_full	Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice
title_fullStr	Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice
title_full_unstemmed	Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice
title_sort	complement c5 is not critical for the formation of sub-rpe deposits in efemp1 mutant mice
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2259019cd6ae4e0484dfbf83b812201a
work_keys_str_mv	AT donitalgarland complementc5isnotcriticalfortheformationofsubrpedepositsinefemp1mutantmice AT ericapierce complementc5isnotcriticalfortheformationofsubrpedepositsinefemp1mutantmice AT rosariofernandezgodino complementc5isnotcriticalfortheformationofsubrpedepositsinefemp1mutantmice
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Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice

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