Retinal Pigment Epithelium Remodeling in Mouse Models of Retinitis Pigmentosa.

Debora Napoli,Beatrice Di Marco,Federico Billeri,Noemi Orsini,Elena Novelli,Martina Biagioni,Enrica Strettoi

doi:10.3390/ijms22105381

Abstract

In retinitis pigmentosa (RP), one of many possible genetic mutations causes rod degeneration, followed by cone secondary death leading to blindness. Accumulating evidence indicates that rod death triggers multiple, non-cell-autonomous processes, which include oxidative stress and inflammation/immune responses, all contributing to cone demise. Inflammation relies on local microglia and recruitment of immune cells, reaching the retina through breakdowns of the inner blood retinal barrier (iBRB). Leakage in the inner retina vasculature suggests similarly altered outer BRB, formed by junctions between retinal pigment epithelium (RPE) cells, which are crucial for retinal homeostasis, immune response, and privilege. We investigated the RPE structural integrity in three models of RP (rd9, rd10, and Tvrm4 mice) by immunostaining for zonula occludens-1 (ZO-1), an essential regulatory component of tight junctions. Quantitative image analysis demonstrated discontinuities in ZO-1 profiles in all mutants, despite different degrees of photoreceptor loss. ZO-1 interruption zones corresponded to leakage of in vivo administered, fluorescent dextran through the choroid-RPE interface, demonstrating barrier dysfunction. Dexamethasone, administered to rd10 mice for rescuing cones, also rescued RPE structure. Thus, previously undetected, stereotyped abnormalities occur in the RPE of RP mice; pharmacological targeting of inflammation supports a feedback loop leading to simultaneous protection of cones and the RPE.

Highlights

The retinal pigment epithelium (RPE) is a monolayer of polygonal cells located between the photoreceptors and the choriocapillaris, delimited by Bruch’s membrane
A close spatial relationship between photoreceptors and RPE cells is common to the lightsensitive organs of both invertebrate and vertebrate animals, and proper photoreceptor physiology depends on interactions between photosensitive and pigmented cells
We studied RPE morphology of rd9 mice, which carry a spontaneous mutation in the retinitis pigmentosa GTPase regulator (RPGR) gene, located on the X chromosome and known to play a key role in the functions of the connecting cilium [13]. rd9 mutants are a rare model of X-linked RP, characterized by a slow phenotype, gradually progressing

Summary

Introduction

The retinal pigment epithelium (RPE) is a monolayer of polygonal cells located between the photoreceptors and the choriocapillaris, delimited by Bruch’s membrane. A close spatial relationship between photoreceptors and RPE cells is common to the lightsensitive organs of both invertebrate and vertebrate animals, and proper photoreceptor physiology depends on interactions between photosensitive and pigmented cells. The regularly tiled RPE cells, typically of hexagonal shape, perform a variety of functions, all relevant for retinal physiology and homeostasis. The RPE delivers nutrients and phagocytes photoreceptor outer segments, disposing and recycling waste products. The RPE is involved in the production and secretion of growth factors, controls the retinal immune response and privilege, and its tight junction complexes are the main constituents of the outer retinal blood barrier (BRB), whose integrity is necessary to protect the retina from exogenous insults and excessive inflammation [1]

Methods

Results

Conclusion