cGAS drives noncanonical-inflammasome activation in age-related macular degeneration

• Published in: Nature medicine Vol. 24; no. 1; pp. 50 - 61
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.01.2018
• Subjects: Accumulation; Activation; Age; Age related diseases; Animal models; Animals; Atrophy; Blindness; Caspase-1; Caspase-11; Caspase-4; Cell culture; Cyclic GMP; DEAD-box RNA Helicases - genetics; Deoxyribonucleic acid; DNA; Epithelium; Eye (anatomy); Eye diseases; Geographic Atrophy - enzymology; Humans; Inflammasomes; Inflammasomes - metabolism; Interferon; Interferon regulatory factor 3; Interferon Type I - metabolism; Interleukin 18; Macular degeneration; Mice; Mitochondrial DNA; Nucleotidyltransferases - metabolism; Retina; Retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; Ribonuclease III - genetics; Ribonucleic acid; RNA; Signal Transduction; Signaling; Target recognition; β-Interferon
• DOI: 10.1038/nm.4450
• ISSN: 1078-8956

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-β 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-β, 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.