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.
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J.A. was supported by NIH grants (DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, and R01EY024068), Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Ellison Medical Foundation Senior Scholar in Aging Award, John Templeton Foundation, Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and DuPont Guerry, III, Professorship; N.K. by NIH (K99EY024336, R00EY024336) and Beckman Initiative for Macular Research (BIMR); B.J.F by NIH T32HL091812 and UL1RR033173; R.Y. by Association for Research in Vision and Ophthalmology (ARVO)/Alcon Early Career Clinician-Scientist Research Award; T.Y. by Fight for Sight postdoctoral award; A.B.C. by the Programme for Advanced Medical Education (sponsored by Fundação Calouste Gulbenkian, Fundação Champalimaud, Ministério da Saúde and Fundação para a Ciência e Tecnologia, Portugal); D.R.H. by NIH R01EY001545 and an unrestricted departmental grant from Research to Prevent Blindness; J.C.C. by NIH R21AI099346; S.F.by Research Grant of Japan Eye Bank Association; S.M.J. by NIH R37AG006168; B.D.G. by American Heart Association and by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000117; V.S. by NIH (T32GM007055; F31DK108553) and N.L. by NIH (R01DK096076, P01 HL120840).
The datasets generated during and/or analyzed during the current study are not publicly available due to commercialization of research findings but are available from the corresponding author on reasonable request.
A Life Sciences Reporting Summary is available.
Supplementary information is available in the online version of the paper.
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; Gelfand, Bradley D.; and Ambati, Jayakrishna, "cGAS Drives Noncanonical-Inflammasome Activation in Age-Related Macular Degeneration" (2018). Ophthalmology and Visual Science Faculty Publications. 13.