Receptor interacting protein kinase-mediated necrosis contributes to cone and rod photoreceptor degeneration in the retina lacking interphotoreceptor retinoid-binding protein

Kota Sato, Songhua Li, William C. Gordon, Jibao He, Gregory I Liou, James M. Hill, Gabriel H. Travis, Nicolas G. Bazan, Minghao Jin

Research output: Contribution to journalArticle

51 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)17458-17468
Number of pages11
JournalJournal of Neuroscience
Volume33
Issue number44
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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