Activated monocytes resist elimination by retinal pigment epithelium and downregulate their OTX2 expression via TNF-α.

Thibaud Mathis,Pauline Gondouin,José‐Alain Sahel,Michael Housset,Sara Touhami,Fanny Beguier,Sebastien Augustin,Xavier Guillonneau,Sacha Reichman,Olivier Goureau,Florian Sennlaub,Laurent Kodjikian,Chiara Eandi

doi:10.1111/acel.12540

Abstract

SummaryOrthodenticle homeobox 2 (OTX2) controls essential, homeostatic retinal pigment epithelial (RPE) genes in the adult. Using cocultures of human CD14+ blood monocytes (Mos) and primary porcine RPE cells and a fully humanized system using human‐induced pluripotent stem cell‐derived RPE cells, we show that activated Mos markedly inhibit RPE OTX2 expression and resist elimination in contact with the immunosuppressive RPE. Mechanistically, we demonstrate that TNF‐α, secreted from activated Mos, mediates the downregulation of OTX2 and essential RPE genes of the visual cycle among others. Our data show how subretinal, chronic inflammation and in particular TNF‐α can affect RPE function, which might contribute to the visual dysfunctions in diseases such as age‐related macular degeneration (AMD) where subretinal macrophages are observed. Our findings provide important mechanistic insights into the regulation of OTX2 under inflammatory conditions. Therapeutic restoration of OTX2 expression might help revive RPE and visual function in retinal diseases such as AMD.

Highlights

Orthodenticle homeobox 2 (OTX2) is a key transcription factor for the development of the brain and sensory organs (Acampora et al, 1995; Cantos et al, 2000; Fossat et al, 2006)
Using cocultures of human CD14+ blood monocytes (Mos) and primary porcine retinal pigment epithelial (RPE) cells and a fully humanized system using humaninduced pluripotent stem cell-derived RPE cells, we show that activated Mos markedly inhibit RPE OTX2 expression and resist elimination in contact with the immunosuppressive RPE
We demonstrate that TNF-a, secreted from activated Mos, mediates the downregulation of OTX2 and essential RPE genes of the visual cycle among others

Summary

Introduction

Orthodenticle homeobox 2 (OTX2) is a key transcription factor for the development of the brain and sensory organs (Acampora et al, 1995; Cantos et al, 2000; Fossat et al, 2006). OTX2 expression is maintained in the adult RPE where it regulates the expression of a number of essential genes such as tyrosinase, and P protein, necessary for RPE melanogenesis to inhibit light back scatter (Martınez-Morales et al, 2003; Housset et al, 2013), and transferrin (TRF), an essential iron transporter (Housset et al, 2013) It regulates genes crucially involved in the retinol visual cycle: transthyretin (TTR), a retinol carrier, and retinol dehydrogenase 5 (RDH5) that re-isomerizes all-trans-retinal into 11-cis-retinal (Housset et al, 2013).

Results

Discussion

Conclusion