Schaefer, Nicole and Rasras, Anas and Ormenisan, Delia M. and Amslinger, Sabine and Enzmann, Volker and Jaegle, Herbert and Pauly, Diana (2021) Complement Factor H-Related 3 Enhanced Inflammation and Complement Activation in Human RPE Cells. FRONTIERS IN IMMUNOLOGY, 12: 769242. ISSN 1664-3224,
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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-alpha 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: | Article |
|---|---|
| Uncontrolled Keywords: | PIGMENT EPITHELIAL-CELLS; GENOME-WIDE ASSOCIATION; RETINAL-PIGMENT; OXIDATIVE STRESS; INTRACELLULAR COMPLEMENT; MACULAR DEGENERATION; SECRETION; BINDS; ACCUMULATION; IL-1-BETA; AMD; complement activation; complosome; FHR-3; inflammation; oxidative stress epitopes; RETC-2; RPE cells FHR-3 alters RPE cell complosome |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Augenheilkunde Chemistry and Pharmacy > Institut für Organische Chemie > Arbeitskreis Dr. Sabine Amslinger |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Aug 2022 12:25 |
| Last Modified: | 23 Aug 2022 12:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46343 |
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