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

Nature Medicine volume 24, pages 50–61 (2018)Cite this article

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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.

References

  1. Wong, W.L. et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health 2, e106–e116 (2014).

    Article  PubMed  Google Scholar 

  2. Ambati, J., Ambati, B.K., Yoo, S.H., Ianchulev, S. & Adamis, A.P. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv. Ophthalmol. 48, 257–293 (2003).

    Article  PubMed  Google Scholar 

  3. Ambati, J., Atkinson, J.P. & Gelfand, B.D. Immunology of age-related macular degeneration. Nat. Rev. Immunol. 13, 438–451 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kaneko, H. et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471, 325–330 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tarallo, V. et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149, 847–859 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Anderson, O.A., Finkelstein, A. & Shima, D.T. A2E induces IL-1ß production in retinal pigment epithelial cells via the NLRP3 inflammasome. PLoS One 8, e67263 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tseng, W.A. et al. NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 54, 110–120 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gelfand, B.D. et al. Iron toxicity in the retina requires Alu RNA and the NLRP3 Inflammasome. Cell Rep. 11, 1686–1693 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kayagaki, N. et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246–1249 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Rathinam, V.A. et al. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150, 606–619 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zanoni, I. et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352, 1232–1236 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Kleinman, M.E. et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452, 591–597 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kleinman, M.E. et al. Short-interfering RNAs induce retinal degeneration via TLR3 and IRF3. Mol. Ther. 20, 101–108 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Kajiwara, Y. et al. A critical role for human caspase-4 in endotoxin sensitivity. J. Immunol. 193, 335–343 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fowler, B.J. et al. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346, 1000–1003 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kerur, N. et al. TLR-independent and P2X7-dependent signaling mediate Alu RNA-induced NLRP3 inflammasome activation in geographic atrophy. Invest. Ophthalmol. Vis. Sci. 54, 7395–7401 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Aglietti, R.A. et al. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc. Natl. Acad. Sci. USA 113, 7858–7863 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim, Y. et al. DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration. Proc. Natl. Acad. Sci. USA 111, 16082–16087 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dunaief, J.L., Dentchev, T., Ying, G.S. & Milam, A.H. The role of apoptosis in age-related macular degeneration. Arch. Ophthalmol. 120, 1435–1442 (2002).

    Article  PubMed  Google Scholar 

  24. van Genderen, H. et al. In vitro measurement of cell death with the annexin A5 affinity assay. Nat. Protoc. 1, 363–367 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Fink, S.L., Bergsbaken, T. & Cookson, B.T. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc. Natl. Acad. Sci. USA 105, 4312–4317 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z.J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Schoggins, J.W. et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505, 691–695 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Feher, J. et al. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol. Aging 27, 983–993 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Terluk, M.R. et al. Investigating mitochondria as a target for treating age-related macular degeneration. J. Neurosci. 35, 7304–7311 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. West, A.P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Galluzzi, L., Blomgren, K. & Kroemer, G. Mitochondrial membrane permeabilization in neuronal injury. Nat. Rev. Neurosci. 10, 481–494 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Baines, C.P. et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658–662 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. McLeod, D.S. et al. Distribution and quantification of choroidal macrophages in human eyes with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 57, 5843–5855 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Sakurai, E., Anand, A., Ambati, B.K., van Rooijen, N. & Ambati, J. Macrophage depletion inhibits experimental choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 44, 3578–3585 (2003).

    Article  PubMed  Google Scholar 

  35. Wang, X. et al. Requirement for microglia for the maintenance of synaptic function and integrity in the mature retina. J. Neurosci. 36, 2827–2842 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Karijolich, J., Abernathy, E. & Glaunsinger, B.A. Infection-induced retrotransposon-derived noncoding RNAs enhance herpesviral gene expression via the NF-κB pathway. PLoS Pathog. 11, e1005260 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. West, A.P., Shadel, G.S. & Ghosh, S. Mitochondria in innate immune responses. Nat. Rev. Immunol. 11, 389–402 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fang, C., Wei, X. & Wei, Y. Mitochondrial DNA in the regulation of innate immune responses. Protein Cell 7, 11–16 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Zhang, Q., Itagaki, K. & Hauser, C.J. Mitochondrial DNA is released by shock and activates neutrophils via p38 map kinase. Shock 34, 55–59 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Yan, Y. et al. Dicer expression exhibits a tissue-specific diurnal pattern that is lost during aging and in diabetes. PLoS One 8, e80029 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hung, T. et al. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression. Science 350, 455–459 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hitomi, J. et al. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβbeta-induced cell death. J. Cell Biol. 165, 347–356 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Katayama, T. et al. Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat. Cell Biol. 1, 479–485 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Yang, D., He, Y., Muñoz-Planillo, R., Liu, Q. & Núñez, G. Caspase-11 requires the Pannexin 1 channel and the purinergic P2X7 pore to mediate pyroptosis and endotoxic shock. Immunity 43, 923–932 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shaw, P.X. et al. Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids. Proc. Natl. Acad. Sci. USA 109, 13757–13762 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Suzuki, M. et al. Oxidized phospholipids in the macula increase with age and in eyes with age-related macular degeneration. Mol. Vis. 13, 772–778 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Brandstetter, C., Mohr, L.K., Latz, E., Holz, F.G. & Krohne, T.U. Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage. J. Mol. Med. (Berl.) 93, 905–916 (2015).

    Article  CAS  Google Scholar 

  52. Kauppinen, A. et al. Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells--implications for age-related macular degeneration (AMD). Immunol. Lett. 147, 29–33 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Marneros, A.G. NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration. Cell Rep. 4, 945–958 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Doyle, S.L. et al. NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nat. Med. 18, 791–798 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wallach, D., Kang, T.B., Dillon, C.P. & Green, D.R. Programmed necrosis in inflammation: toward identification of the effector molecules. Science 352, aaf2154 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Man, S.M. & Kanneganti, T.D. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat. Rev. Immunol. 16, 7–21 (2016).

    Article  CAS  PubMed  Google Scholar 

  57. Hirano, Y. et al. IL-18 is not therapeutic for neovascular age-related macular degeneration. Nat. Med. 20, 1372–1375 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ambati, J. & Fowler, B.J. Mechanisms of age-related macular degeneration. Neuron 75, 26–39 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mariathasan, S. et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213–218 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Kanneganti, T.D. et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440, 233–236 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Müller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994).

    PubMed  Google Scholar 

  62. Sato, M. et al. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity 13, 539–548 (2000).

    CAS  PubMed  Google Scholar 

  63. Suschak, J.J., Wang, S., Fitzgerald, K.A. & Lu, S. A cGAS-independent STING/IRF7 pathway mediates the immunogenicity of DNA vaccines. J. Immunol. 196, 310–316 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. Jin, L. et al. MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP. J. Immunol. 187, 2595–2601 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Bennett, E.A. et al. Active Alu retrotransposons in the human genome. Genome Res. 18, 1875–1883 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Shaikh, T.H., Roy, A.M., Kim, J., Batzer, M.A. & Deininger, P.L. cDNAs derived from primary and small cytoplasmic Alu (scAlu) transcripts. J. Mol. Biol. 271, 222–234 (1997).

    Article  CAS  PubMed  Google Scholar 

  67. Nagai, H. et al. Gene transfer of secreted-type modified interleukin-18 gene to B16F10 melanoma cells suppresses in vivo tumor growth through inhibition of tumor vessel formation. J. Invest. Dermatol. 119, 541–548 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Huang, J. et al. Comparison of noncontact specular and confocal microscopy for evaluation of corneal endothelium. Eye Contact Lens https://doi.org/10.1097/ICL.0000000000000362 (2017).

  69. Laing, R.A., Sanstrom, M.M., Berrospi, A.R. & Leibowitz, H.M. Changes in the corneal endothelium as a function of age. Exp. Eye Res. 22, 587–594 (1976).

    Article  CAS  PubMed  Google Scholar 

  70. Doughty, M.J., Müller, A. & Zaman, M.L. Assessment of the reliability of human corneal endothelial cell-density estimates using a noncontact specular microscope. Cornea 19, 148–158 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Inaba, M., Matsuda, M., Shiozaki, Y. & Kosaki, H. Regional specular microscopy of endothelial cell loss after intracapsular cataract extraction: a preliminary report. Acta Ophthalmol. (Copenh.) 63, 232–235 (1985).

    Article  CAS  Google Scholar 

  72. Laing, R.A., Sandstrom, M.M. & Leibowitz, H.M. In vivo photomicrography of the corneal endothelium. Arch. Ophthalmol. 93, 143–145 (1975).

    Article  CAS  PubMed  Google Scholar 

  73. Ach, T. et al. Lipofuscin redistribution and loss accompanied by cytoskeletal stress in retinal pigment epithelium of eyes with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 56, 3242–3252 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dridi, S. et al. ERK1/2 activation is a therapeutic target in age-related macular degeneration. Proc. Natl. Acad. Sci. USA 109, 13781–13786 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Grossniklaus, H.E., Nickerson, J.M., Edelhauser, H.F., Bergman, L.A. & Berglin, L. Anatomic alterations in aging and age-related diseases of the eye. Invest. Ophthalmol. Vis. Sci. 54, ORSF23–ORSF7 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Bannwarth, S., Procaccio, V. & Paquis-Flucklinger, V. Rapid identification of unknown heteroplasmic mutations across the entire human mitochondrial genome with mismatch-specific Surveyor Nuclease. Nat. Protoc. 1, 2037–2047 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Yang, P., Tyrrell, J., Han, I. & Jaffe, G.J. Expression and modulation of RPE cell membrane complement regulatory proteins. Invest. Ophthalmol. Vis. Sci. 50, 3473–3481 (2009).

    Article  PubMed  Google Scholar 

  78. Miceli, M.V. & Jazwinski, S.M. Nuclear gene expression changes due to mitochondrial dysfunction in ARPE-19 cells: implications for age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 46, 1765–1773 (2005).

    Article  PubMed  Google Scholar 

  79. Kagan, V.E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017).

    Article  CAS  PubMed  Google Scholar 

  80. Wang, X. et al. Polydatin, a natural polyphenol, protects arterial smooth muscle cells against mitochondrial dysfunction and lysosomal destabilization following hemorrhagic shock. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R805–R814 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Bonora, M. et al. Comprehensive analysis of mitochondrial permeability transition pore activity in living cells using fluorescence-imaging-based techniques. Nat. Protoc. 11, 1067–1080 (2016).

    Article  CAS  PubMed  Google Scholar 

Download references

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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Authors and Affiliations

  1. Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA

    Nagaraj Kerur, Shinichi Fukuda, Daipayan Banerjee, Younghee Kim, Dongxu Fu, Ivana Apicella, Akhil Varshney, Reo Yasuma, Kameshwari Ambati, Shuichiro Hirahara, Bradley D Gelfand & Jayakrishna Ambati

  2. Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA

    Nagaraj Kerur, Shinichi Fukuda, Daipayan Banerjee, Younghee Kim, Dongxu Fu, Ivana Apicella, Akhil Varshney, Reo Yasuma, Kameshwari Ambati, Shuichiro Hirahara, Bradley D Gelfand & Jayakrishna Ambati

  3. Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA

    Nagaraj Kerur, Daipayan Banerjee, Younghee Kim, Reo Yasuma, Benjamin J Fowler, Kameshwari Ambati, Ana Bastos-Carvalho, Bradley D Gelfand & Jayakrishna Ambati

  4. Department of Ophthalmology, University of Tsukuba, Ibaraki, Japan

    Shinichi Fukuda, Tetsuhiro Yasuma, Yoshio Hirano & Tetsuro Oshika

  5. Doheny Eye Institute, Los Angeles, Los Angeles, California, USA

    Elmira Baghdasaryan, Kenneth M Marion, Xiwen Huang & SriniVas R Sadda

  6. Department of Ophthalmology, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA

    Elmira Baghdasaryan & SriniVas R Sadda

  7. Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Tetsuhiro Yasuma & Hiroko Terasaki

  8. Department of Ophthalmology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Yoshio Hirano & Yuichiro Ogura

  9. Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA

    Vlad Serbulea & Norbert Leitinger

  10. Center for Digital Image Evaluation, Charlottesville, Virginia, USA

    Meenakshi Ambati & Vidya L Ambati

  11. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Yuji Kajiwara & Joseph D Buxbaum

  12. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, USA

    Kyung Bo Kim

  13. Departments of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA

    David R Hinton

  14. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA

    John C Cambier

  15. Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, USA

    M Cristina Kenney

  16. Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA

    S Michal Jazwinski

  17. Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan

    Hiroshi Nagai

  18. Department of Urology, Wakayama Medical University, Wakayama, Japan

    Isao Hara

  19. Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, USA

    A Phillip West

  20. Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Katherine A Fitzgerald

  21. Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, Virginia, USA

    Bradley D Gelfand

  22. Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA

    Jayakrishna Ambati

  23. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA

    Jayakrishna Ambati

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  1. Nagaraj Kerur
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Contributions

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.

Corresponding authors

Correspondence to Nagaraj Kerur or Jayakrishna Ambati.

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Competing interests

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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