Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

Y. Murakami, H. Matsumoto, M. Roh, A. Giani, K. Kataoka, Yuki Morizane, M. Kayama, A. Thanos, S. Nakatake, S. Notomi, T. Hisatomi, Y. Ikeda, T. Ishibashi, K. M. Connor, J. W. Miller, D. G. Vavvas

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I: C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3-/-mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I: C)-induced retinal degeneration. Moreover, after poly(I: C) injection, Rip3-/-mice displayed decreased levels of pro-inflammatory cytokines (such as TNF- and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I: C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF- and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF- and IL-6 production after poly(I: C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.

Original languageEnglish
Pages (from-to)270-277
Number of pages8
JournalCell Death and Differentiation
Volume21
Issue number2
DOIs
Publication statusPublished - Feb 2014
Externally publishedYes

Fingerprint

Retinal Degeneration
Macular Degeneration
Necrosis
Retinal Pigment Epithelium
Apoptosis
Inflammation
Interleukin-6
Retina
Macrophages
Receptor-Interacting Protein Serine-Threonine Kinases
Biological Phenomena
Injections
Protein Kinases
Cell Death
polyriboinosinic-polyribocytidylic acid
Cytokines
Therapeutics

Keywords

  • degeneration
  • macula
  • necrosis
  • neuroprotection
  • retina

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. / Murakami, Y.; Matsumoto, H.; Roh, M.; Giani, A.; Kataoka, K.; Morizane, Yuki; Kayama, M.; Thanos, A.; Nakatake, S.; Notomi, S.; Hisatomi, T.; Ikeda, Y.; Ishibashi, T.; Connor, K. M.; Miller, J. W.; Vavvas, D. G.

In: Cell Death and Differentiation, Vol. 21, No. 2, 02.2014, p. 270-277.

Research output: Contribution to journalArticle

Murakami, Y, Matsumoto, H, Roh, M, Giani, A, Kataoka, K, Morizane, Y, Kayama, M, Thanos, A, Nakatake, S, Notomi, S, Hisatomi, T, Ikeda, Y, Ishibashi, T, Connor, KM, Miller, JW & Vavvas, DG 2014, 'Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration', Cell Death and Differentiation, vol. 21, no. 2, pp. 270-277. https://doi.org/10.1038/cdd.2013.109
Murakami, Y. ; Matsumoto, H. ; Roh, M. ; Giani, A. ; Kataoka, K. ; Morizane, Yuki ; Kayama, M. ; Thanos, A. ; Nakatake, S. ; Notomi, S. ; Hisatomi, T. ; Ikeda, Y. ; Ishibashi, T. ; Connor, K. M. ; Miller, J. W. ; Vavvas, D. G. / Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. In: Cell Death and Differentiation. 2014 ; Vol. 21, No. 2. pp. 270-277.
@article{cef8c9362e784d038c88420c194a26fb,
title = "Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration",
abstract = "There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I: C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3-/-mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I: C)-induced retinal degeneration. Moreover, after poly(I: C) injection, Rip3-/-mice displayed decreased levels of pro-inflammatory cytokines (such as TNF- and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I: C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF- and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF- and IL-6 production after poly(I: C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.",
keywords = "degeneration, macula, necrosis, neuroprotection, retina",
author = "Y. Murakami and H. Matsumoto and M. Roh and A. Giani and K. Kataoka and Yuki Morizane and M. Kayama and A. Thanos and S. Nakatake and S. Notomi and T. Hisatomi and Y. Ikeda and T. Ishibashi and Connor, {K. M.} and Miller, {J. W.} and Vavvas, {D. G.}",
year = "2014",
month = "2",
doi = "10.1038/cdd.2013.109",
language = "English",
volume = "21",
pages = "270--277",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

AU - Murakami, Y.

AU - Matsumoto, H.

AU - Roh, M.

AU - Giani, A.

AU - Kataoka, K.

AU - Morizane, Yuki

AU - Kayama, M.

AU - Thanos, A.

AU - Nakatake, S.

AU - Notomi, S.

AU - Hisatomi, T.

AU - Ikeda, Y.

AU - Ishibashi, T.

AU - Connor, K. M.

AU - Miller, J. W.

AU - Vavvas, D. G.

PY - 2014/2

Y1 - 2014/2

N2 - There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I: C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3-/-mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I: C)-induced retinal degeneration. Moreover, after poly(I: C) injection, Rip3-/-mice displayed decreased levels of pro-inflammatory cytokines (such as TNF- and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I: C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF- and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF- and IL-6 production after poly(I: C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.

AB - There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I: C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3-/-mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I: C)-induced retinal degeneration. Moreover, after poly(I: C) injection, Rip3-/-mice displayed decreased levels of pro-inflammatory cytokines (such as TNF- and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I: C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF- and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF- and IL-6 production after poly(I: C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.

KW - degeneration

KW - macula

KW - necrosis

KW - neuroprotection

KW - retina

UR - http://www.scopus.com/inward/record.url?scp=84892439582&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892439582&partnerID=8YFLogxK

U2 - 10.1038/cdd.2013.109

DO - 10.1038/cdd.2013.109

M3 - Article

VL - 21

SP - 270

EP - 277

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

SN - 1350-9047

IS - 2

ER -