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

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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

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Keywords

  • degeneration
  • macula
  • necrosis
  • neuroprotection
  • retina

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

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, K. M., Miller, J. W., & Vavvas, D. G. (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, 21(2), 270-277. https://doi.org/10.1038/cdd.2013.109