title: Receptor interacting protein kinase-mediated necrosis contributes to cone and rod photoreceptor degeneration in the retina lacking interphotoreceptor retinoid-binding protein.
abstract: Interphotoreceptor retinoid-binding protein (IRBP) secreted by photoreceptors plays a pivotal role in photoreceptor survival with an unknown mechanism. A mutation in the human IRBP has been linked to retinitis pigmentosa, a progressive retinal degenerative disease. Mice lacking IRBP display severe early and progressive photoreceptor degeneration. However, the signaling pathway(s) leading to photoreceptor death in IRBP-deficient mice remains poorly understood. Here, we show that amounts of tumor necrosis factor-α (TNF-α) in the interphotoreceptor matrix and retinas of Irbp(-/-) mice were increased more than 10-fold and fivefold, respectively, compared with those in wild-type mice. Moreover, TNF-α receptor 1, an important membrane death receptor that mediates both programmed apoptosis and necrosis, was also significantly increased in Irbp(-/-) retina, and was colocalized with peanut agglutinin to the Irbp(-/-) cone outer segments. Although these death signaling proteins were increased, the caspase-dependent and independent apoptotic pathways were mildly activated in the Irbp(-/-) retinas, suggesting that other cell death mechanism(s) also contributes to the extensive photoreceptor degeneration in Irbp(-/-) retina. We found that receptor interacting protein 1 and 3 (RIP1 and RIP3) kinases, the intracellular key mediators of TNF-induced cellular necrosis, were elevated at least threefold in the Irbp(-/-) retinas. Moreover, pharmacological inhibition of RIP1 kinase significantly prevented cone and rod photoreceptor degeneration in Irbp(-/-) mice. These results reveal that RIP kinase-mediated necrosis strongly contributes to cone and rod degeneration in Irbp(-/-) mice, implicating the TNF-RIP pathway as a potential therapeutic target to prevent or delay photoreceptor degeneration in patients with retinitis pigmentosa caused by IRBP mutation.
authors.affiliation: Department of Ophthalmology and Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, Electron Microscope Laboratory, Tulane University, New Orleans, Louisiana 70118, Department of Ophthalmology, Georgia Health Sciences University, Augusta, Georgia 30912, and Jules Stein Eye Institute, The University of California, Los Angeles School of Medicine, Los Angeles, California 90095.
authors.forename: Kota
authors.initials: K
authors.lastname: Sato
authors.forename: Songhua
authors.initials: S
authors.lastname: Li
authors.forename: William C
authors.initials: WC
authors.lastname: Gordon
authors.forename: Jibao
authors.initials: J
authors.lastname: He
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Liou
authors.forename: James M
authors.initials: JM
authors.lastname: Hill
authors.forename: Gabriel H
authors.initials: GH
authors.lastname: Travis
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Bazan
authors.forename: Minghao
authors.initials: M
authors.lastname: Jin
mesh_terms: D000818:Animals; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009336:Necrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012177:Retinol-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D005136:Eye Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse