Enhanced apoptosis in retinal pigment epithelium under inflammatory stimuli and oxidative stress.
Age-related macular degeneration (AMD) is a neurodegenerative disease that causes irreversible central vision loss in the elderly. Retinal pigment epithelium (RPE) has been found to be a key component in AMD pathogenesis. The Ccl2(-/-)/Cx3cr1(-/-) (DKO) mouse on Crb1(rd8) background is created as an AMD model, developing AMD-like retinal lesions. Our study aimed to examine RPE apoptosis in DKO mouse and human ARPE-19 cell line. DKO RPE expressed higher apoptotic proteins when compared with age-matched wild type (WT) RPE in physiological conditions. Apoptosis of primary cultured mouse RPE was evaluated under stimulation with lipopolysaccharide for inflammatory stimulation and 2,3,7,8-tetrachlorodibenzo-p-dioxin or H(2)O(2) for oxidative stress. Compared with WT RPE, DKO RPE was more susceptible to Fas ligand (FasL)-mediated apoptosis under both inflammatory and oxidative stress, with less cell viability and higher expression of apoptotic transcripts and proteins. Decreased cell viability was also observed in ARPE-19 cells under each stimulus. Furthermore, we also investigated the anti-apoptotic effects of decoy receptor 3 (DcR3), a decoy receptor for FasL, on ARPE-19 cells under inflammatory and oxidative stress. DcR3 pre-incubated ARPE-19 cells showed decreased apoptosis, with increased cell viability and decreased expression of apoptotic transcripts and proteins under the stimuli. On the contrary, knockdown of DcR3 in ARPE-19 cells showed totally opposite results. Our study demonstrates that FasL-mediated RPE apoptosis may play a pivotal role in AMD pathogenesis.
Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Dr., 10/10N103, NIH/NEI, Bethesda, MD 20892-1857, USA.
Yujuan
Y
Wang
Defen
D
Shen
Vinson M
VM
Wang
Cheng-Rong
CR
Yu
Ren-Xi
RX
Wang
Jingsheng
J
Tuo
Chi-Chao
CC
Chan
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D008070:Lipopolysaccharides; D000072317:Polychlorinated Dibenzodioxins; D034741:RNA, Small Interfering; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C505911:TNFRSF6B protein, human