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dc.contributor.authorMurakami, Y
dc.contributor.authorMatsumoto, Hidetaka
dc.contributor.authorRoh, Mi In
dc.contributor.authorGiani, A
dc.contributor.authorKataoka, Keiko
dc.contributor.authorMorizane, Y
dc.contributor.authorKayama, M
dc.contributor.authorThanos, Aristomenis
dc.contributor.authorNakatake, S
dc.contributor.authorNotomi, S
dc.contributor.authorHisatomi, T
dc.contributor.authorIkeda, Y
dc.contributor.authorIshibashi, T
dc.contributor.authorConnor, K M
dc.contributor.authorMiller, Joan Whitten
dc.contributor.authorVavvas, Demetrios
dc.date.accessioned2018-03-16T15:45:24Z
dc.date.issued2013
dc.identifierQuick submit: 2013-09-06T02:26:33-04:00
dc.identifier.citationMurakami, 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.en_US
dc.identifier.issn1350-9047en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:34961435
dc.description.abstractThere 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_US
dc.language.isoen_USen_US
dc.publisherSpringer Natureen_US
dc.relation.isversionof10.1038/cdd.2013.109en_US
dash.licenseOAP
dc.titleProgrammed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degenerationen_US
dc.typeJournal Articleen_US
dc.date.updated2013-09-06T06:27:08Z
dc.description.versionAccepted Manuscripten_US
dc.rights.holderY 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 Vavvas
dc.relation.journalCell Death & Differentiationen_US
dash.depositing.authorVavvas, Demetrios
dc.date.available2018-03-16T15:45:24Z
dc.identifier.doi10.1038/cdd.2013.109*
dash.authorsorderedfalse
dash.contributor.affiliatedMatsumoto, Hidetaka
dash.contributor.affiliatedKataoka, Keiko
dash.contributor.affiliatedThanos, Aristomenis
dash.contributor.affiliatedRoh, Mi In
dash.contributor.affiliatedMiller, Joan
dash.contributor.affiliatedVavvas, Demetrios


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