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cGAS drives noncanonical-inflammasome activation in age-related macular degeneration.
Kerur, Nagaraj; Fukuda, Shinichi; Banerjee, Daipayan; Kim, Younghee; Fu, Dongxu; Apicella, Ivana; Varshney, Akhil; Yasuma, Reo; Fowler, Benjamin J; Baghdasaryan, Elmira; Marion, Kenneth M; Huang, Xiwen; Yasuma, Tetsuhiro; Hirano, Yoshio; Serbulea, Vlad; Ambati, Meenakshi; Ambati, Vidya L; Kajiwara, Yuji; Ambati, Kameshwari; Hirahara, Shuichiro; Bastos-Carvalho, Ana; Ogura, Yuichiro; Terasaki, Hiroko; Oshika, Tetsuro; Kim, Kyung Bo; Hinton, David R; Leitinger, Norbert; Cambier, John C; Buxbaum, Joseph D; Kenney, M Cristina; Jazwinski, S Michal; Nagai, Hiroshi; Hara, Isao; West, A Phillip; Fitzgerald, Katherine A; Sadda, SriniVas R; Gelfand, Bradley D; Ambati, Jayakrishna.
Afiliação
  • Kerur N; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Fukuda S; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Banerjee D; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA.
  • Kim Y; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Fu D; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Apicella I; Department of Ophthalmology, University of Tsukuba, Ibaraki, Japan.
  • Varshney A; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Yasuma R; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Fowler BJ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA.
  • Baghdasaryan E; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Marion KM; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Huang X; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA.
  • Yasuma T; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Hirano Y; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Serbulea V; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Ambati M; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Ambati VL; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Kajiwara Y; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Ambati K; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Hirahara S; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Bastos-Carvalho A; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA.
  • Ogura Y; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA.
  • Terasaki H; Doheny Eye Institute, Los Angeles, Los Angeles, California, USA.
  • Oshika T; Department of Ophthalmology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.
  • Kim KB; Doheny Eye Institute, Los Angeles, Los Angeles, California, USA.
  • Hinton DR; Doheny Eye Institute, Los Angeles, Los Angeles, California, USA.
  • Leitinger N; Department of Ophthalmology, University of Tsukuba, Ibaraki, Japan.
  • Cambier JC; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Buxbaum JD; Department of Ophthalmology, University of Tsukuba, Ibaraki, Japan.
  • Kenney MC; Department of Ophthalmology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  • Jazwinski SM; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Nagai H; Center for Digital Image Evaluation, Charlottesville, Virginia, USA.
  • Hara I; Center for Digital Image Evaluation, Charlottesville, Virginia, USA.
  • West AP; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • Fitzgerald KA; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Sadda SR; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Gelfand BD; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA.
  • Ambati J; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Nat Med ; 24(1): 50-61, 2018 01.
Article em En | MEDLINE | ID: mdl-29176737
ABSTRACT
Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-ß production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-ß, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Atrofia Geográfica / Inflamassomos / Nucleotidiltransferases Limite: Animals / Humans Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Atrofia Geográfica / Inflamassomos / Nucleotidiltransferases Limite: Animals / Humans Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos