cGAS drives non-canonical inflammasome activation in age-related macular degeneration
| Autor: | Nagaraj Kerur, S. Michal Jazwinski, John C. Cambier, Katherine A. Fitzgerald, Tetsuhiro Yasuma, Shinichi Fukuda, Vidya L. Ambati, Reo Yasuma, Isao Hara, Jayakrishna Ambati, Srinivas R. Sadda, Ivana Apicella, Tetsuro Oshika, Bradley D. Gelfand, Meenakshi Ambati, Kyung Bo Kim, Elmira Baghdasaryan, Hiroshi Nagai, Yuichiro Ogura, Akhil Varshney, Yuji Kajiwara, Dongxu Fu, Norbert Leitinger, A. Phillip West, Kameshwari Ambati, Yoshio Hirano, Kenneth M. Marion, Daipayan Banerjee, Benjamin J. Fowler, Joseph D. Buxbaum, Vlad Serbulea, Younghee Kim, Hiroko Terasaki, Xiwen Huang, Ana Bastos-Carvalho, David R. Hinton, M. Cristina Kenney, Shuichiro Hirahara |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Ribonuclease III Inflammasomes Degeneration (medical) Retinal Pigment Epithelium Biology General Biochemistry Genetics and Molecular Biology Article DEAD-box RNA Helicases 03 medical and health sciences Mice 0302 clinical medicine Interferon Geographic Atrophy medicine Animals Humans Secretion Retina RNA Inflammasome General Medicine Anatomy Macular degeneration medicine.disease Nucleotidyltransferases Cell biology 030104 developmental biology medicine.anatomical_structure Interferon Type I Signal transduction 030217 neurology & neurosurgery medicine.drug Signal Transduction |
| Zdroj: | Nature medicine |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | Geographic atrophy is a blinding form of age-related macular degeneration characterized by death of the retinal pigmented epithelium (RPE). In this disease, the RPE displays evidence of 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 in mouse models is driven by a non-canonical inflammasome pathway that results in activation of caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β (IFN-β) production and gasdermin D-dependent interleukin-18 (IL-18) secretion. Reduction of DICER1 levelsor accumulation of Alu RNA triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, IFN-β, and cGAS levels are elevated in the RPE of human eyes with geographic atrophy. Collectively, these data highlight an unexpected role for 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 non-infectious human disease, and identify new potential targets for treatment of a major cause of blindness. |
| Databáze: | OpenAIRE |
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