Schäfer, Nicole; Rasras, Anas; Ormenisan, Delia M; Amslinger, Sabine; Enzmann, Volker; Jägle, Herbert; Pauly, Diana (2021). Complement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells. Frontiers in immunology, 12, p. 769242. Frontiers Research Foundation 10.3389/fimmu.2021.769242
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ophthalmology 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Augenklinik > Forschungsgruppe Augenheilkunde |
UniBE Contributor: |
Enzmann, Volker |
Subjects: |
600 Technology > 610 Medicine & health 500 Science > 570 Life sciences; biology |
ISSN: |
1664-3224 |
Publisher: |
Frontiers Research Foundation |
Language: |
English |
Submitter: |
Volker Enzmann |
Date Deposited: |
05 Jan 2022 17:19 |
Last Modified: |
05 Dec 2022 15:56 |
Publisher DOI: |
10.3389/fimmu.2021.769242 |
PubMed ID: |
34819935 |
Uncontrolled Keywords: |
AMD FHR-3 RETC-2 RPE cells FHR-3 alters RPE cell complosome complement activation complosome inflammation oxidative stress epitopes |
BORIS DOI: |
10.48350/162198 |
URI: |
https://boris.unibe.ch/id/eprint/162198 |
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