Enhanced apoptosis in retinal pigment epithelium under inflammatory stimuli and oxidative stress

• DOI: 10.1007/s10495-012-0750-1
• Publication Date: 2012-08-21T08:17:56Z
• Authors: Yujuan Wang; Defen Shen; Vinson M. Wang; Cheng-Rong Yu; Ren-Xi Wang; Jingsheng Tuo; Chi-Chao Chan
• Keywords: Inflammation; Lipopolysaccharides; Mice, Knockout; 0301 basic medicine; Polychlorinated Dibenzodioxins; Receptors, Tumor Necrosis Factor, Member 6b; Apoptosis; Retinal Pigment Epithelium; Mitochondria; Mice; Oxidative Stress; 03 medical and health sciences; Microscopy, Fluorescence; Gene Knockdown Techniques; Animals; Humans; RNA, Small Interfering; Cells, Cultured

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.