Murakami, YMatsumoto, HidetakaRoh, Mi InGiani, AKataoka, KeikoMorizane, YKayama, MThanos, AristomenisNakatake, SNotomi, SHisatomi, TIkeda, YIshibashi, TConnor, K MMiller, JoanVavvas, Demetrios2018-03-162013Murakami, Y, H Matsumoto, M Roh, A Giani, K Kataoka, Y Morizane, M Kayama, et al. 2013. “Programmed Necrosis, Not Apoptosis, Is a Key Mediator of Cell Loss and DAMP-Mediated Inflammation in dsRNA-Induced Retinal Degeneration.” Cell Death & Differentiation 21 (2) (August 16): 270–277. doi:10.1038/cdd.2013.109.1350-9047http://nrs.harvard.edu/urn-3:HUL.InstRepos:34961435There 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.en-USJournal Article2013-09-06Y Murakami, H Matsumoto, M Roh, A Giani, K Kataoka, Y Morizane, M Kayama, A Thanos, S Nakatake, S Notomi, T Hisatomi, Y Ikeda, T Ishibashi, K M Connor, J W Miller, and D G Vavvas2018-03-1610.1038/cdd.2013.109