Evidence for ceramide induced cytotoxicity in retinal ganglion cells.

Autor: Fan J; Storm Eye Institute, Medical University of South Carolina, Department of Ophthalmology, 167 Ashley Ave, Charleston, SC, 29425, USA. Electronic address: fan@musc.edu., Liu J; Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Department of Ophthalmology, 274 Middle Zhijiang Road, Jingan District, Shanghai, 200071, China., Liu J; Storm Eye Institute, Medical University of South Carolina, Department of Ophthalmology, 167 Ashley Ave, Charleston, SC, 29425, USA., Chen C; Storm Eye Institute, Medical University of South Carolina, Department of Ophthalmology, 167 Ashley Ave, Charleston, SC, 29425, USA., Koutalos Y; Storm Eye Institute, Medical University of South Carolina, Department of Ophthalmology, 167 Ashley Ave, Charleston, SC, 29425, USA., Crosson CE; Storm Eye Institute, Medical University of South Carolina, Department of Ophthalmology, 167 Ashley Ave, Charleston, SC, 29425, USA.
Jazyk: angličtina
Zdroj: Experimental eye research [Exp Eye Res] 2021 Oct; Vol. 211, pp. 108762. Date of Electronic Publication: 2021 Sep 07.
DOI: 10.1016/j.exer.2021.108762
Abstrakt: Ceramides are bioactive compounds that play important roles in regulating cellular responses to extracellular stimuli and stress. Previous studies have shown that ceramides contribute to retinal degeneration associated with ischemic and ocular hypertensive stress. Acid sphingomyelinase (ASMase) is one of the major enzymes responsible for the stress-induced generation of ceramides. The goals of this study are to investigate the effects of ceramides on retinal ganglion cells (RGCs) and of ASMase inhibition in ocular hypertensive mice. Induced pluripotent stem cell (iPSC)-derived RGCs and primary cultures of human optic nerve head astrocytes were used to characterize the response to C2-ceramide. Microbead-induced ocular hypertension in the ASMase heterozygote mouse model was used to confirm the physiological relevance of in vitro studies. In mice, RGC function and morphology were assessed with pattern ERG (pERG) and immunofluorescence. The addition of C2-ceramide to iPSC-derived RGCs produced a significant concentration- and time-dependent reduction in cell numbers when compared to control cultures. While the addition of C2-ceramide to astrocytes did not affect viability, it resulted in a 2.6-fold increase in TNF-α secretion. The addition of TNF-α or conditioned media from C2-ceramide-treated astrocytes to RGC cultures significantly reduced cell numbers by 56.1 ± 8.4% and 24.7 ± 4.8%, respectively. This cytotoxic response to astrocyte-conditioned media was blocked by TNF-α antibody. In ASMase heterozygote mice, functional and morphological analyses of ocular hypertensive eyes reveal significantly less RGC degeneration when compared with hypertensive eyes from wild-type mice. These results provide evidence that ceramides can induce RGC cell death by acting directly, as well as indirectly via the secretion of TNF-α from optic nerve head astrocytes. In vivo studies in mice provide evidence that ceramides derived through the activity of ASMase contribute to ocular hypertensive injury. Together these results support the importance of ceramides in the pathogenesis of ocular hypertensive injury to the retina.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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