June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Retinal atrophy phenotypes associated with light sensitivity and inflammation in the new MerTK-cleavage resistant mouse model
Author Affiliations & Notes
  • Emeline F Nandrot
    Institut de la vision, Paris, Île-de-France, France
  • Salomé Réty
    Institut de la vision, Paris, Île-de-France, France
  • Julie Enderlin
    Institut de la vision, Paris, Île-de-France, France
  • Quentin Rieu
    Institut de la vision, Paris, Île-de-France, France
  • Sébastien Augustin
    Institut de la vision, Paris, Île-de-France, France
  • Elora Vanoni
    Institut de la vision, Paris, Île-de-France, France
  • Solène Roux
    Institut de la vision, Paris, Île-de-France, France
  • Ira Tabas
    Columbia University, New York, New York, United States
  • Florian Sennlaub
    Institut de la vision, Paris, Île-de-France, France
  • Footnotes
    Commercial Relationships   Emeline Nandrot None; Salomé Réty None; Julie Enderlin None; Quentin Rieu None; Sébastien Augustin None; Elora Vanoni None; Solène Roux None; Ira Tabas None; Florian Sennlaub None
  • Footnotes
    Support  LABEX LIFESENSES [ANR-10-LABX-65, project grant to EFN], IHU FOReSIGHT [ANR-18-IAHU-0001, project grant to EFN]
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1938 – F0356. doi:
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      Emeline F Nandrot, Salomé Réty, Julie Enderlin, Quentin Rieu, Sébastien Augustin, Elora Vanoni, Solène Roux, Ira Tabas, Florian Sennlaub; Retinal atrophy phenotypes associated with light sensitivity and inflammation in the new MerTK-cleavage resistant mouse model. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1938 – F0356.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The MerTK tyrosine kinase receptor is a key element of the retinal pigment epithelial (RPE) phagocytic machinery required for photoreceptors (PRs) survival. Recently, we showed this receptor is subjected to the cleavage of its extracellular domain as a way of finely controlling its function. We thus investigated the ocular phenotype of MerTK cleavage-resistant (MerTKCR) mice devoid of the cleavage site.

Methods : MerTKCR and control mice were monitored between the ages of 3 and 18 months using fundus photography (FP), autofluorescence (AF) detection, optical coherence tomography (OCT), electroretinography (ERG), optokinetic behavioral tests as well as paraffin-embedded and electron microscopy (EM) tissue sections. Survival of bone-marrow macrophages (BMMs) was assessed in pig primary RPE co-cultures. Mitochondrial activity and energy sources use were evaluated with the Seahorse technology on freshly-dissected RPE/choroid and retina tissues.

Results : Our first cohorts showed large degenerative areas in the central retina associated with AF, in males and then in females, only when followed monthly by OCT plus FP/AF but not by OCT alone. We thus hypothesize that MerTKCR mice might be light-sensitized by the FP and AF lamp bulbs. Besides thinning of the photoreceptor layer, macrophages infiltration was observed by OCT. Though, MerTKCR BMMs do not survive more than controls in primary RPE co-cultures, suggesting that observed macrophages could be linked to decreased RPE immunosuppressivity rather than to increased BMMs survival potential. At the EM level, RPE anomalies were detected including phagosomes retained in the apical area and abnormal mitochondria. Accordingly, mitochondrial function and energy production are reduced in RPE/choroid tissues.

Conclusions : Current experiments are testing which cell type carries the light sensitivity, assessing macrophages infiltration after laser impacts and exploring in vivo BMMs survival after adoptive cross-transfers between MerTKCR and control mice. As well, the RPE phagocytic profile is being explored both in vitro and in vivo. All together, this new mouse model displays a novel phenotype that could prove useful to understand the interplay between RPE and PRs in inflammatory retinal degenerations and highlight a new role for MerTK in the maintenance of the immune privilege in the retina.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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