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

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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-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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Figure 1: Caspase-4/11 in geographic atrophy and RPE degeneration.
Figure 2: Gasdermin D in geographic atrophy and RPE degeneration.
Figure 3: Noncanonical-inflammasome activation and RPE degeneration induced by Alu RNA is mediated by IFN signaling.
Figure 4: cGAS-driven signaling licenses the noncanonical inflammasome and degeneration of the RPE.
Figure 5: cGAS in geographic atrophy and RPE degeneration.
Figure 6: mtDNA in noncanonical-inflammasome activation and RPE degeneration.

Change history

  • 01 January 2018

    In the version of this article initially published online, a micrograph in Figure 1d (WT, Vehicle) and a micrograph in Figure 2a (Gsdmd−/−, Alu RNA) are duplicates of two other micrographs and are incorrect. These errors do not affect the quantitative data reported or the conclusions of the article. These two micrographs have been replaced with the correct ones in the print, PDF and HTML versions of this article.

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Acknowledgements

We thank Z. Chen, V. Tarallo, and P. Pinton for valuable discussions. We thank H. Virgin (Washington University in St. Louis), G. Shadel (Yale University), W. T. Wong (NIH), L. Zhao (NIH), and V. Dixit (Genentech) for reagents. We thank G. Pattison, E. Ghias, K. Langberg, D. Robertson, E. Doswell, X. Zhou, K. Atwood, R. Makin, O. Kirillina, A. Bobrov, E. Dinning, L. Pandya, C. Payne, G. Botzet, N. Bell, R. King, L. Xu, L. Toll, and A. Uittenbogaard for technical assistance, and the University of Kentucky Viral Core (COBRE) for providing lentiviral vectors. J.A. was supported by NIH grants (DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, and R01EY024068), a Doris Duke Distinguished Clinical Scientist Award, a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, an Ellison Medical Foundation Senior Scholar in Aging Award, and the John Templeton Foundation; as the Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair; and through a DuPont Guerry, III Professorship. N.K. was supported by NIH grants K99EY024336 and R00EY024336, and the Beckman Initiative for Macular Research (BIMR). S.F. was supported by a Research Grant from the Japan Eye Bank Association and Society for the Promotion of Science (JSPS) Overseas Research Fellowship. B.J.F. was supported by NIH grants T32HL091812 and UL1RR033173. R.Y. was supported by an Association for Research in Vision and Ophthalmology (ARVO)/Alcon Early Career Clinician-Scientist Research Award. T.Y. was supported by a Fight for Sight postdoctoral award. A.B.-C. was supported 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. was supported by NIH R01EY001545 and an unrestricted departmental grant from Research to Prevent Blindness. J.C.C. was supported by NIH R21AI099346. S.F. was supported by a Research Grant from the Japan Eye Bank Association. S.M.J. was supported by NIH R37AG006168. B.D.G. was supported by the 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. was supported by NIH grants T32GM007055 and F31DK108553. N.L. was supported by NIH grants R01DK096076 and P01 HL120840. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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N.K., S.F., D.B., Y. Kim, D.F., I.A., A.V., R.Y., B.J.F., E.B., K.M.M., X.H., T.Y., Y.H., V.S., M.A., V.L.A., N.L., K.A., S.H., A.B.-C., and B.D.G. performed experiments or analyzed data. Y. Kajiwara, D.R.H., J.C.C., J.D.B., A.P.W., S.M.J., M.C.K., K.A.F., K.B.K., Y.O., H.T., H.N., I.H., and T.O. contributed mice, tissues or reagents. J.A. and N.K. conceived and directed the project, and wrote the paper with assistance from B.J.F., B.D.G., N.L., K.A., and S.R.S. All authors had the opportunity to discuss the results and comment on the manuscript.

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Correspondence to Nagaraj Kerur or Jayakrishna Ambati.

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J.A. is a cofounder of iVeena Holdings, iVeena Pharmaceuticals, iVeena Delivery Systems, and Inflammasome Therapeutics, and has been a consultant for Allergan, Biogen, and Olix Pharmaceuticals in a capacity unrelated to this work. J.A., N.K., B.J.F., and K.A. are named as inventors on patent applications on macular degeneration filed by the University of Kentucky or the University of Virginia.

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Kerur, N., Fukuda, S., Banerjee, D. et al. cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat Med 24, 50–61 (2018). https://doi.org/10.1038/nm.4450

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