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

Y Murakami1, H Matsumoto2, M Roh2

  • 11] Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA [2] Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Cell Death and Differentiation
|August 20, 2013
PubMed

Insights

Receptor-interacting protein (RIP) kinase mediates necrosis and inflammation in a mouse model of age-related macular degeneration (AMD). RIP3 deficiency prevented retinal degeneration, suggesting it as a therapeutic target for AMD.

Area of Science:

  • Ophthalmology
  • Immunology
  • Cell Biology

Background:

  • Age-related macular degeneration (AMD) lacks effective treatments, with cell death and inflammation implicated in its progression.
  • Drusen, a hallmark of AMD, contain double-stranded RNA (dsRNA).

Purpose of the Study:

  • To investigate the role of receptor-interacting protein (RIP) kinase in dsRNA-induced retinal degeneration and inflammation.
  • To explore RIP3 as a potential therapeutic target for dry AMD.

Main Methods:

  • A mouse model of retinal degeneration induced by poly(I:C) (a dsRNA analog).
  • Assessment of retinal pigment epithelium (RPE) necrosis, macrophage infiltration, and pro-inflammatory cytokine levels (TNF-α, IL-6).
  • Evaluation of high-mobility group box-1 (HMGB1) release in Rip3-deficient mice and cells.

Main Results:

  • Poly(I:C) induced RPE necrosis and inflammation in wild-type mice, but this was prevented in Rip3(-/-) mice.
  • Rip3 deficiency reduced pro-inflammatory cytokine levels and HMGB1 release in the retina.
  • In vitro studies confirmed that Rip3 deficiency inhibited dsRNA-induced RPE necrosis and subsequent inflammatory mediator release.

Conclusions:

  • Programmed necrosis mediated by RIP3 is critical in dsRNA-induced retinal degeneration.
  • RIP3-dependent necrosis promotes inflammation by regulating damage-associated molecular pattern (DAMP) release.
  • Targeting RIP kinase offers a potential therapeutic strategy for AMD.

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