Journal
CELL DEATH AND DIFFERENTIATION
Volume 21, Issue 2, Pages 270-277Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2013.109
Keywords
retina; neuroprotection; necrosis; macula; degeneration
Categories
Funding
- Research to Prevent Blindness Physician Scientist Award
- NIH [NEI R21EY023079-01A1, R01EY022084-01/S1]
- Foundation Lions Eye Research Fund
- Onassis Foundation
- Yeatts Family Foundation
- Rena Family Foundation
- Bausch & Lomb Vitreoretinal Fellowship
- NEI grant [EY014104]
- Japanese Ministry of Education, Culture, Sports, Science, and Technology grant [25861637]
- Grants-in-Aid for Scientific Research [25861637] Funding Source: KAKEN
Ask authors/readers for more resources
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-alpha 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-alpha and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF-alpha 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available