title: Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration.
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.
authors: 1] Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA [2] Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Y
authors: Y
authors: Murakami
authors: Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: H
authors: H
authors: Matsumoto
authors: Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: M
authors: M
authors: Roh
authors: Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: A
authors: A
authors: Giani
authors: Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: K
authors: K
authors: Kataoka
authors: Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: Y
authors: Y
authors: Morizane
authors: Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: M
authors: M
authors: Kayama
authors: Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: A
authors: A
authors: Thanos
authors: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: S
authors: S
authors: Nakatake
authors: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: S
authors: S
authors: Notomi
authors: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: T
authors: T
authors: Hisatomi
authors: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Y
authors: Y
authors: Ikeda
authors: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: T
authors: T
authors: Ishibashi
authors: Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: K M
authors: KM
authors: Connor
authors: Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: J W
authors: JW
authors: Miller
authors: Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: D G
authors: DG
authors: Vavvas
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology*; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000187:drug effects / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology
chemical_list: D012330:RNA, Double-Stranded; D051192:Receptors, Pattern Recognition; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D011070:Poly I-C
references: J Exp Med. 2003 Jul 7;198(1):161-71
references: 12835481
references: J Biol Chem. 2011 Apr 29;286(17):15543-55
references: 21383019
references: Cell. 2010 Mar 19;140(6):798-804
references: 20303871
references: Nat Genet. 2011 Sep 11;43(10):1001-4
references: 21909106
references: Nature. 2011 Sep 14;477(7364):335-9
references: 21921917
references: Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):296-301
references: 14695889
references: Arch Ophthalmol. 1999 Mar;117(3):329-39
references: 10088810
references: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12611-6
references: 20616036
references: Br J Ophthalmol. 2010 Jul;94(7):918-25
references: 19965817
references: Am J Ophthalmol. 1986 Mar 15;101(3):342-53
references: 3953728
references: Science. 2009 Jul 17;325(5938):332-6
references: 19498109
references: Nature. 2011 Jan 13;469(7329):221-5
references: 21124315
references: Cell Host Microbe. 2010 Apr 22;7(4):302-313
references: 20413098
references: Nat Med. 2012 Jun;18(6):911-7
references: 22610280
references: Science. 2005 Apr 15;308(5720):419-21
references: 15761120
references: Invest Ophthalmol Vis Sci. 2007 Jul;48(7):3341-9
references: 17591907
references: N Engl J Med. 2008 Oct 2;359(14):1456-63
references: 18753640
references: Science. 1999 Jul 9;285(5425):248-51
references: 10398600
references: Immunity. 2011 Dec 23;35(6):908-18
references: 22195746
references: Eye (Lond). 1988;2 ( Pt 5):552-77
references: 2476333
references: Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21695-700
references: 21098270
references: Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3915-21
references: 19339734
references: J Biol Chem. 2005 Nov 4;280(44):36560-6
references: 16115877
references: Arch Ophthalmol. 2004 Apr;122(4):477-85
references: 15078664
references: Cell. 2009 Jun 12;137(6):1100-11
references: 19524512
references: Nat Immunol. 2000 Dec;1(6):489-95
references: 11101870
references: Nat Rev Immunol. 2005 Apr;5(4):331-42
references: 15803152
references: Nature. 2011 Mar 17;471(7338):368-72
references: 21368762
references: Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11900-5
references: 16079201
references: Immunity. 2011 May 27;34(5):637-50
references: 21616434
references: Mol Cell. 2011 Aug 5;43(3):449-63
references: 21737330
references: J Exp Med. 2008 Oct 27;205(11):2609-21
references: 18838547
references: Cell. 2012 Jul 20;150(2):339-50
references: 22817896
references: Mol Cell Biol. 2004 Feb;24(4):1464-9
references: 14749364
references: Prog Retin Eye Res. 2009 Nov;28(6):393-422
references: 19698799
references: Nat Med. 2008 Feb;14(2):194-8
references: 18223656
references: Invest Ophthalmol Vis Sci. 1996 Jun;37(7):1236-49
references: 8641827
references: Nature. 2011 Mar 17;471(7338):363-7
references: 21368763
references: Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14598-603
references: 22908283
references: Cell. 2009 Jun 12;137(6):1112-23
references: 19524513
references: Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20054-9
references: 22123964
references: Arch Ophthalmol. 2009 Apr;127(4):483-92
references: 19365029
references: Nature. 2011 Mar 17;471(7338):325-30
references: 21297615
references: Nature. 2011 Jul 31;477(7364):330-4
references: 21804564
references: N Engl J Med. 2008 Jun 12;358(24):2606-17
references: 18550876
references: Nature. 2002 Jul 11;418(6894):191-5
references: 12110890
references: Nat Med. 2009 Nov;15(11):1318-21
references: 19855397
references: Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2425-30
references: 17284607
references: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20388-93
references: 19918053
references: Lab Invest. 2009 Mar;89(3):278-89
references: 19139725
references: Nat Rev Mol Cell Biol. 2010 Oct;11(10):700-14
references: 20823910