Article ; Online: Retinal Pigment Epithelial Cells Mitigate the Effects of Complement Attack by Endocytosis of C5b-9.
Journal of immunology (Baltimore, Md. : 1950)
2015 Volume 195, Issue 7, Page(s) 3382–3389
Abstract: Retinal pigment epithelial (RPE) cell death is a hallmark of age-related macular degeneration. The alternative pathway of complement activation is strongly implicated in RPE cell dysfunction and loss in age-related macular degeneration; therefore, it is ... ...
| Abstract | Retinal pigment epithelial (RPE) cell death is a hallmark of age-related macular degeneration. The alternative pathway of complement activation is strongly implicated in RPE cell dysfunction and loss in age-related macular degeneration; therefore, it is critical that RPE cells use molecular strategies to mitigate the potentially harmful effects of complement attack. We show that the terminal complement complex C5b-9 assembles rapidly on the basal surface of cultured primary porcine RPE cells but disappears over 48 h without any discernable adverse effects on the cells. However, in the presence of the dynamin inhibitor dynasore, C5b-9 was almost completely retained at the cell surface, suggesting that, under normal circumstances, it is eliminated via the endocytic pathway. In support of this idea, we observed that C5b-9 colocalizes with the early endosome marker EEA1 and that, in the presence of protease inhibitors, it can be detected in lysosomes. Preventing the endocytosis of C5b-9 by RPE cells led to structural defects in mitochondrial morphology consistent with cell stress. We conclude that RPE cells use the endocytic pathway to prevent the accumulation of C5b-9 on the cell surface and that processing and destruction of C5b-9 by this route are essential for RPE cell survival. |
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| MeSH term(s) | Animals ; Cell Membrane/metabolism ; Cells, Cultured ; Complement Activation/immunology ; Complement Membrane Attack Complex/immunology ; Dynamins/antagonists & inhibitors ; Endocytosis/immunology ; Epithelial Cells/cytology ; Epithelial Cells/immunology ; Hydrazones/pharmacology ; Macular Degeneration/immunology ; Macular Degeneration/pathology ; Mitochondria/pathology ; Protein Transport/immunology ; Retinal Pigment Epithelium/cytology ; Retinal Pigment Epithelium/immunology ; Swine ; Vesicular Transport Proteins/metabolism | ||||||||||
| Chemical Substances | Complement Membrane Attack Complex ; Hydrazones ; N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide ; Vesicular Transport Proteins ; early endosome antigen 1 ; Dynamins (EC 3.6.5.5) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2015-08-31 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 3056-9 | ||||||||||
| ISSN | 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381 | ||||||||||
| ISSN (online) | 1550-6606 | ||||||||||
| ISSN | 0022-1767 ; 1048-3233 ; 1047-7381 | ||||||||||
| DOI | 10.4049/jimmunol.1500937 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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