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-α 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-α and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF-α 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.
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Abbreviations
- AMD:
-
age-related macular degeneration
- DAMPs:
-
damage-associated molecular patterns
- GCL:
-
ganglion cell layer
- HMGB1:
-
high-mobility group box 1
- INL:
-
inner nuclear layer
- LPS:
-
lipopolysaccharide
- Nec-1:
-
necrostatin-1
- ONL:
-
outer nuclear layer
- RIP:
-
receptor-interacting protein
- RPE:
-
retinal pigment epithelium
- TLRs:
-
toll-like receptors
- TEM:
-
transmission electron microscopy
- WT:
-
wild type
- ZO-1:
-
zona occludens 1
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Acknowledgements
We thank N Michaud (MEEI) and F Morikawa (Kyushu U) for technical assistance, and W Chao (MEEI) for her support in critical review. This work was supported by Research to Prevent Blindness Physician Scientist Award (DGV), NIH NEI R21EY023079-01A1 (DGV) Foundation Lions Eye Research Fund (DGV), Onassis Foundation (DGV), The Yeatts Family Foundation (JWM , DGV), Rena Family Foundation (JWM, DGV), Bausch & Lomb Vitreoretinal Fellowship (HM, Y Morizane and KM), NEI grant EY014104 (MEEI Core Grant), NIH R01EY022084–01/S1 (KMC) and the Japanese Ministry of Education, Culture, Sports, Science, and Technology grant 25861637 (Y. Murakami).
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Murakami, Y., Matsumoto, H., Roh, M. et al. Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. Cell Death Differ 21, 270–277 (2014). https://doi.org/10.1038/cdd.2013.109
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DOI: https://doi.org/10.1038/cdd.2013.109
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