title: Activated monocytes resist elimination by retinal pigment epithelium and downregulate their OTX2 expression via TNF-α.
abstract: Orthodenticle 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 RPEOTX2 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.
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.|Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of medicine Lyon 1, 103 Grande rue de la Croix Rousse, 69317, Lyon Cedex 04, France.
authors.forename: Thibaud
authors.initials: T
authors.lastname: Mathis
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Housset
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.|Department of Clinical Science, Eye Clinic, University of Torino, Torino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Eandi
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Beguier
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Touhami
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.
authors.forename: Sacha
authors.initials: S
authors.lastname: Reichman
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Augustin
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Gondouin
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of medicine Lyon 1, 103 Grande rue de la Croix Rousse, 69317, Lyon Cedex 04, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Kodjikian
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Goureau
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Guillonneau
authors.affiliation: Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|UPMC University of Paris 06, INSERM, CNRS, Sorbonne Universités, Paris, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
mesh_terms: D000818:Animals; D015536:Down-Regulation; D006801:Humans; D009000:Monocytes / Q000473:pathology*; D051857:Otx Transcription Factors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology*; D034421:Sus scrofa; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051857:Otx Transcription Factors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha
keywords: OTX2; TNF-α; age-related macular degeneration; monocytes; retinal pigment epithelium; visual cycle