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

46 Citations (Scopus)

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 - Nov 4 2013

Fingerprint

Receptor-Interacting Protein Serine-Threonine Kinases
Retinal Cone Photoreceptor Cells
Retinal Rod Photoreceptor Cells
Protein Kinases
Retina
Necrosis
Retinitis Pigmentosa
Phosphotransferases
Tumor Necrosis Factor-alpha
Peanut Agglutinin
Retinal Diseases
Death Domain Receptors
Mutation
Tumor Necrosis Factor Receptors
Caspases
Cell Death
Cone-Rod Dystrophies
interstitial retinol-binding protein
Pharmacology
Apoptosis

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Receptor interacting protein kinase-mediated necrosis contributes to cone and rod photoreceptor degeneration in the retina lacking interphotoreceptor retinoid-binding protein. / Sato, Kota; Li, Songhua; Gordon, William C.; He, Jibao; Liou, Gregory I; Hill, James M.; Travis, Gabriel H.; Bazan, Nicolas G.; Jin, Minghao.

In: Journal of Neuroscience, Vol. 33, No. 44, 04.11.2013, p. 17458-17468.

Research output: Contribution to journalArticle

Sato, Kota ; Li, Songhua ; Gordon, William C. ; He, Jibao ; Liou, Gregory I ; Hill, James M. ; Travis, Gabriel H. ; Bazan, Nicolas G. ; Jin, Minghao. / Receptor interacting protein kinase-mediated necrosis contributes to cone and rod photoreceptor degeneration in the retina lacking interphotoreceptor retinoid-binding protein. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 44. pp. 17458-17468.
@article{188c88b45a724cf7b71ceb3100699bae,
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.",
author = "Kota Sato and Songhua Li and Gordon, {William C.} and Jibao He and Liou, {Gregory I} and Hill, {James M.} and Travis, {Gabriel H.} and Bazan, {Nicolas G.} and Minghao Jin",
year = "2013",
month = "11",
day = "4",
doi = "10.1523/JNEUROSCI.1380-13.2013",
language = "English (US)",
volume = "33",
pages = "17458--17468",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "44",

}

TY - JOUR

T1 - Receptor interacting protein kinase-mediated necrosis contributes to cone and rod photoreceptor degeneration in the retina lacking interphotoreceptor retinoid-binding protein

AU - Sato, Kota

AU - Li, Songhua

AU - Gordon, William C.

AU - He, Jibao

AU - Liou, Gregory I

AU - Hill, James M.

AU - Travis, Gabriel H.

AU - Bazan, Nicolas G.

AU - Jin, Minghao

PY - 2013/11/4

Y1 - 2013/11/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84886686848&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886686848&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.1380-13.2013

DO - 10.1523/JNEUROSCI.1380-13.2013

M3 - Article

C2 - 24174679

AN - SCOPUS:84886686848

VL - 33

SP - 17458

EP - 17468

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 44

ER -