Schustak, Joshua, Han, Hongwei, Bond, Kyle, Huang, Qian, Saint-Geniez, Magali and Bao, Yi (2024) Phenotypic high-throughput screening identifies aryl hydrocarbon receptor agonism as common inhibitor of toxin-induced retinal pigment epithelium cell death. PloS one, 19 (4). e0301239. ISSN 1932-6203

Abstract

The retinal pigment epithelium (RPE) is essential to maintain retinal function, and RPE cell death represents a key pathogenic stage in the progression of several blinding ocular diseases, including age-related macular degeneration (AMD). To identify pathways and compounds able to prevent RPE cell death, we developed a phenotypic screening pipeline utilizing a compound library and high-throughput screening compatible assays on the human RPE cell line, ARPE-19, in response to different disease relevant cytotoxic stimuli. We show that the metabolic by-product of the visual cycle all-trans-retinal (atRAL) induces RPE apoptosis, while the lipid peroxidation by-product 4-hydroxynonenal (4-HNE) promotes necrotic cell death. Using these distinct stimuli for screening, we identified agonists of the aryl hydrocarbon receptor (AhR) as a consensus target able to prevent both atRAL mediated apoptosis and 4-HNE-induced necrotic cell death. This works serves as a framework for future studies dedicated to screening for inhibitors of cell death, as well as support for the discussion of AhR agonism in RPE pathology.

Item Type:	Article
Keywords:	Humans Retinal Pigment Epithelium High-Throughput Screening Assays Receptors, Aryl Hydrocarbon Apoptosis Cell Death Oxidative Stress
Date Deposited:	14 May 2024 00:45
Last Modified:	14 May 2024 00:45
URI:	https://oak.novartis.com/id/eprint/50312