@article {1351172,
	title = {Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration},
	journal = {Cell Death Differ},
	volume = {21},
	number = {2},
	year = {2014},
	month = {2014 Feb},
	pages = {270-7},
	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. },
	keywords = {Animals, Apoptosis, Cell Death, Cell Survival, Cells, Cultured, Inflammation, Mice, Mice, Inbred C57BL, Mice, Knockout, Necrosis, Poly I-C, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Pattern Recognition, Retinal Pigment Epithelium, RNA, Double-Stranded},
	issn = {1476-5403},
	doi = {10.1038/cdd.2013.109},
	author = {Murakami, Y and Matsumoto, H and Roh, M and Giani, A and Kataoka, K and Morizane, Y and Kayama, M and Thanos, A and Nakatake, S and Notomi, S and Hisatomi, T and Ikeda, Y and Ishibashi, T and Connor, K M and Miller, J W and Vavvas, D G}
}
