Oxidative stress sensitizes retinal pigmented epithelial (RPE) cells to complement-mediated injury in a natural antibody-, lectin pathway-, and phospholipid epitope-dependent manner
| العنوان: | Oxidative stress sensitizes retinal pigmented epithelial (RPE) cells to complement-mediated injury in a natural antibody-, lectin pathway-, and phospholipid epitope-dependent manner |
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| المؤلفون: | V. Michael Holers, Beth Coughlin, Steffen Thiel, Kannan Kunchithapautham, Liudmila Kulik, Bärbel Rohrer, Nicole M. Thielens, Mausumi Bandyopadhyay, Kusumam Joseph |
| المساهمون: | Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Thomas, Frank, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) |
| المصدر: | Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2013, 288 (18), pp.12753-65 Joseph, K, Kulik, L, Coughlin, B, Kunchithapautham, K, Bandyopadhyay, M, Thiel, S, Thielens, N M, Holers, V M & Rohrer, B 2013, ' Oxidative stress sensitizes retinal pigmented epithelial (RPE) cells to complement-mediated injury in a natural antibody-, lectin pathway-, and phospholipid epitope-dependent manner ', Journal of Biological Chemistry, vol. 288, no. 18, pp. 12753-65 . https://doi.org/10.1074/jbc.M112.421891Test Journal of Biological Chemistry, 2013, 288 (18), pp.12753-65 |
| بيانات النشر: | HAL CCSD, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | MESH: Complement Pathway, Mannose-Binding Lectin, MESH: Complement C1q, genetic structures, Complement Pathway, Alternative, Retinal Pigment Epithelium, Biochemistry, MESH: Mice, Knockout, Mice, 0302 clinical medicine, MESH: Oxidants, MESH: Animals, Complement C1q, Phospholipids, Mannan-binding lectin, Mice, Knockout, 0303 health sciences, MESH: Oxidative Stress, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Oxidants, MESH: Immunoglobulin M, MESH: Retinal Pigment Epithelium, 3. Good health, Cell biology, Lectin pathway, Factor H, MESH: Hydrogen Peroxide, Ficolin, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Immunology, Biology, Cell Line, 03 medical and health sciences, MESH: Homeodomain Proteins, Animals, Humans, Molecular Biology, MESH: Mice, 030304 developmental biology, Homeodomain Proteins, MESH: Phospholipids, MESH: Humans, Complement Pathway, Mannose-Binding Lectin, Cell Biology, Hydrogen Peroxide, eye diseases, Complement system, MESH: Cell Line, Oxidative Stress, Immunoglobulin M, 030221 ophthalmology & optometry, Alternative complement pathway, sense organs, Complement membrane attack complex, MESH: Complement Pathway, Alternative |
| الوصف: | International audience; Uncontrolled activation of the alternative complement pathway (AP) is thought to be associated with age-related macular degeneration. Previously, we have shown that in retinal pigmented epithelial (RPE) monolayers, oxidative stress reduced complement inhibition on the cell surface, resulting in sublytic complement activation and loss of transepithelial resistance (TER), but the potential ligand and pathway involved are unknown. ARPE-19 cells were grown as monolayers on transwell plates, and sublytic complement activation was induced with H2O2 and normal human serum. TER deteriorated rapidly in H2O2-exposed monolayers upon adding normal human serum. Although the effect required AP activation, AP was not sufficient, because elimination of MASP, but not C1q, prevented TER reduction. Reconstitution experiments to unravel essential components of the lectin pathway (LP) showed that both ficolin and mannan-binding lectin can activate the LP through natural IgM antibodies (IgM-C2) that recognize phospholipid cell surface modifications on oxidatively stressed RPE cells. The same epitopes were found on human primary embryonic RPE monolayers. Likewise, mouse laser-induced choroidal neovascularization, an injury that involves LP activation, could be increased in antibody-deficient rag1(-/-) mice using the phospholipid-specific IgM-C2. In summary, using a combination of depletion and reconstitution strategies, we have shown that the LP is required to initiate the complement cascade following natural antibody recognition of neoepitopes, which is then further amplified by the AP. LP activation is triggered by IgM bound to phospholipids. Taken together, we have defined novel mechanisms of complement activation in oxidatively stressed RPE, linking molecular events involved in age-related macular degeneration, including the presence of natural antibodies and neoepitopes. |
| اللغة: | English |
| تدمد: | 0021-9258 1083-351X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2ac7a4b3de08eedf1fcfd9d4711a76f1Test https://hal.univ-grenoble-alpes.fr/hal-01322432Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2ac7a4b3de08eedf1fcfd9d4711a76f1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00219258 1083351X |
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