P2X7-pannexin-1 and amyloid β-induced oxysterol input in human retinal cell: Role in age-related macular degeneration?
Age-related macular degeneration (AMD) is the most common cause of severe vision loss worldwide. Amyloid β involvement in degenerative diseases such as AMD is well known and its toxicity has been related to P2X7 receptor-pannexin-1. Recently, oxysterols (oxidized derivatives of cholesterol) have been implicated in AMD pathogenesis. The aim of our study was to highlight amyloid β/oxysterols relationship and to describe P2X7 receptor-pannexin-1 role in oxysterols toxicity. Using retinal epithelial cells, we first quantified sterols levels after amyloid β incubation and second we investigated the cytotoxic effects induced by oxysterols. For the first time, our results showed that amyloid β induced oxysterols formation in human retinal pigmented epithelial cells. We showed that oxysterol toxicity is mediated by P2X7 receptor activation. This activation was dependent on pannexin-1 with 25-hydroxycholesterol whereas P2X7 receptor signaling pathway was pannexin-1-independent for 7-ketocholesterol. Taken together our data suggest a pivotal role of P2X7 receptor-pannexin-1 in oxysterols toxicity in retinal cells which could be an important target to develop new treatments for AMD.
UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, 75006 Paris, France; Soliance-Givaudan, Route de Bazancourt, 51110 Pomacle, France.
Elodie
E
Olivier
UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, 75006 Paris, France; Recherche et Développement, Laboratoire d'Evaluation Physiologique, Yslab, 2 Rue Félix le Dantec, 29000 Quimper, France.
Mélody
M
Dutot
UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, 75006 Paris, France.
Anne
A
Regazzetti
UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, 75006 Paris, France.
Teddy
T
Leguillier
UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, 75006 Paris, France.
Delphine
D
Dargère
UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, 75006 Paris, France.
Nicolas
N
Auzeil
UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, 75006 Paris, France.
Olivier
O
Laprévote
UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, 75006 Paris, France. Electronic address: patrice.rat@parisdescartes.fr.
Patrice
P
Rat
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002460:Cell Line; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D017630:Connexins / Q000378:metabolism*; D006801:Humans; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology*; D009336:Necrosis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D000072376:Oxysterols / Q000633:toxicity*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D012160:Retina / Q000378:metabolism / Q000473:pathology*
D016229:Amyloid beta-Peptides; D002843:Chromatin; D017630:Connexins; D009419:Nerve Tissue Proteins; D000072376:Oxysterols; C492764:PANX1 protein, human; D058486:Receptors, Purinergic P2X7
Degenerative disease; Eye/retina; Lipids; Receptors; Toxicology