Chronic exposure to tumor necrosis factor alpha induces retinal pigment epithelium cell dedifferentiation

Sara Touhami,Emeline F Nandrot,Hugo Charles-Messance,Thibaud Mathis,Valérie Forster,Xavier Guillonneau,Florian Sennlaub,José-Alain Sahel,Sacha Reichman,Sébastien Augustin,Lucile Vignaud,Fanny Beguier,Bahram Bodaghi

doi:10.1186/s12974-018-1106-8

Abstract

BackgroundThe retinal pigment epithelium (RPE) is a monolayer of pigmented cells with important barrier and immuno-suppressive functions in the eye. We have previously shown that acute stimulation of RPE cells by tumor necrosis factor alpha (TNFα) downregulates the expression of OTX2 (Orthodenticle homeobox 2) and dependent RPE genes. We here investigated the long-term effects of TNFα on RPE cell morphology and key functions in vitro.MethodsPrimary porcine RPE cells were exposed to TNFα (at 0.8, 4, or 20 ng/ml per day) for 10 days. RPE cell morphology, phagocytosis, barrier- and immunosuppressive-functions were assessed.ResultsChronic (10 days) exposure of primary RPE cells to TNFα increases RPE cell size and polynucleation, decreases visual cycle gene expression, impedes RPE tight-junction organization and transepithelial resistance, and decreases the immunosuppressive capacities of the RPE. TNFα-induced morphological- and transepithelial-resistance changes were prevented by concomitant Transforming Growth Factor β inhibition.ConclusionsOur results indicate that chronic TNFα-exposure is sufficient to alter RPE morphology and impede cardinal features that define the differentiated state of RPE cells with striking similarities to the alterations that are observed with age in neurodegenerative diseases such as age-related macular degeneration.

Highlights

The retinal pigment epithelium (RPE) is a monolayer of pigmented cells with important barrier and immuno-suppressive functions in the eye
Using a co-culture model, we recently demonstrated that Mφ-derived tumor necrosis factor alpha (TNFα) acutely downregulates the transcription factor orthodenticle homeobox 2 (OTX2) that is constitutively expressed in RPE cells, where it controls the expression of a number of essential genes
Taken together our results indicate that chronic Tumor necrosis factor alpha (TNFα) exposure is sufficient to alter RPE morphology and impede cardinal features that define the differentiated state of RPE cells with striking similarities to RPE alterations with age and dysfunctions observed in age-related macular degeneration (AMD)

Summary

Introduction

The retinal pigment epithelium (RPE) is a monolayer of pigmented cells with important barrier and immuno-suppressive functions in the eye. The retinal pigment epithelium (RPE) is a monolayer of polarized pigmented cells, located between the photoreceptor outer segments (POS) and the choroid. These highly differentiated cells play a crucial role in the visual cycle, the recycling of POS, the formation of the outer blood-retinal barrier [1], and in providing immunosuppressive signals that eliminate infiltrating immune cells from the subretinal space [2]. Irregularly shaped, multinucleated RPE cells are found in increased numbers in the vicinity of drusen that define early intermediate age-related macular degeneration (AMD) [5]. It seems evident that RPE dysfunction and death is a pivotal part of AMD pathogenesis, it is not yet clear what leads to and aggravates the decay

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