Complement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells

Complement Factor H-Related 3 (FHR-3) is a major regulator of the complement system, which is associated with different diseases, such as age-related macular degeneration (AMD). However, the non-canonical local, cellular functions of FHR-3 remained poorly understood. Here, we report that FHR-3 bound...

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Autores principales:	Nicole Schäfer, Anas Rasras, Delia M. Ormenisan, Sabine Amslinger, Volker Enzmann, Herbert Jägle, Diana Pauly
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	AMD complement activation complosome FHR-3 inflammation oxidative stress epitopes Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/04e4a6fe38e44a64a7d7be9d64f821b8
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spelling	oai:doaj.org-article:04e4a6fe38e44a64a7d7be9d64f821b82021-11-08T06:44:15ZComplement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells1664-322410.3389/fimmu.2021.769242https://doaj.org/article/04e4a6fe38e44a64a7d7be9d64f821b82021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.769242/fullhttps://doaj.org/toc/1664-3224Complement Factor H-Related 3 (FHR-3) is a major regulator of the complement system, which is associated with different diseases, such as age-related macular degeneration (AMD). However, the non-canonical local, cellular functions of FHR-3 remained poorly understood. Here, we report that FHR-3 bound to oxidative stress epitopes and competed with FH for interaction. Furthermore, FHR-3 was internalized by viable RPE cells and modulated time-dependently complement component (C3, FB) and receptor (C3aR, CR3) expression of human RPE cells. Independently of any external blood-derived proteins, complement activation products were detected. Anaphylatoxin C3a was visualized in treated cells and showed a translocation from the cytoplasm to the cell membrane after FHR-3 exposure. Subsequently, FHR-3 induced a RPE cell dependent pro-inflammatory microenvironment. Inflammasome NLRP3 activation and pro-inflammatory cytokine secretion of IL-1ß, IL-18, IL-6 and TNF-α were induced after FHR-3-RPE interaction. Our previously published monoclonal anti-FHR-3 antibody, which was chimerized to reduce immunogenicity, RETC-2-ximab, ameliorated the effect of FHR-3 on ARPE-19 cells. Our studies suggest FHR-3 as an exogenous trigger molecule for the RPE cell “complosome” and as a putative target for a therapeutic approach for associated degenerative diseases.Nicole SchäferNicole SchäferAnas RasrasAnas RasrasDelia M. OrmenisanSabine AmslingerVolker EnzmannHerbert JägleDiana PaulyDiana PaulyFrontiers Media S.A.articleAMDcomplement activationcomplosomeFHR-3inflammationoxidative stress epitopesImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	AMD complement activation complosome FHR-3 inflammation oxidative stress epitopes Immunologic diseases. Allergy RC581-607
spellingShingle	AMD complement activation complosome FHR-3 inflammation oxidative stress epitopes Immunologic diseases. Allergy RC581-607 Nicole Schäfer Nicole Schäfer Anas Rasras Anas Rasras Delia M. Ormenisan Sabine Amslinger Volker Enzmann Herbert Jägle Diana Pauly Diana Pauly Complement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells
description	Complement Factor H-Related 3 (FHR-3) is a major regulator of the complement system, which is associated with different diseases, such as age-related macular degeneration (AMD). However, the non-canonical local, cellular functions of FHR-3 remained poorly understood. Here, we report that FHR-3 bound to oxidative stress epitopes and competed with FH for interaction. Furthermore, FHR-3 was internalized by viable RPE cells and modulated time-dependently complement component (C3, FB) and receptor (C3aR, CR3) expression of human RPE cells. Independently of any external blood-derived proteins, complement activation products were detected. Anaphylatoxin C3a was visualized in treated cells and showed a translocation from the cytoplasm to the cell membrane after FHR-3 exposure. Subsequently, FHR-3 induced a RPE cell dependent pro-inflammatory microenvironment. Inflammasome NLRP3 activation and pro-inflammatory cytokine secretion of IL-1ß, IL-18, IL-6 and TNF-α were induced after FHR-3-RPE interaction. Our previously published monoclonal anti-FHR-3 antibody, which was chimerized to reduce immunogenicity, RETC-2-ximab, ameliorated the effect of FHR-3 on ARPE-19 cells. Our studies suggest FHR-3 as an exogenous trigger molecule for the RPE cell “complosome” and as a putative target for a therapeutic approach for associated degenerative diseases.
format	article
author	Nicole Schäfer Nicole Schäfer Anas Rasras Anas Rasras Delia M. Ormenisan Sabine Amslinger Volker Enzmann Herbert Jägle Diana Pauly Diana Pauly
author_facet	Nicole Schäfer Nicole Schäfer Anas Rasras Anas Rasras Delia M. Ormenisan Sabine Amslinger Volker Enzmann Herbert Jägle Diana Pauly Diana Pauly
author_sort	Nicole Schäfer
title	Complement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells
title_short	Complement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells
title_full	Complement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells
title_fullStr	Complement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells
title_full_unstemmed	Complement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells
title_sort	complement factor h-related 3 enhanced inflammation and complement activation in human rpe cells
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/04e4a6fe38e44a64a7d7be9d64f821b8
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_version_	1718442874467516416

Complement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells

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