Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome

Bradley D. Gelfand, Charles B. Wright, Younghee Kim, Tetsuhiro Yasuma, Reo Yasuma, Shengjian Li, Benjamin J. Fowler, Ana Bastos-Carvalho, Nagaraj Kerur, Annette Uittenbogaard, Youn Seon Han, Dingyuan Lou, Mark E. Kleinman, W. Hayes McDonald, Gabriel Núñez, Philippe Georgel, Joshua L. Dunaief, Jayakrishna Ambati

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fenton's reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components caspase-1/11 or Nlrp3 or by inhibition of caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting Alu or B2 RNA prevents iron-induced inflammasome activation and RPE degeneration. Iron-induced SINE RNA accumulation is due to suppression of DICER1 via sequestration of the co-factor poly(C)-binding protein 2 (PCBP2). These findings reveal an unexpected mechanism of iron toxicity, with implications for AMD and neurodegenerative diseases associated with excess iron. Iron overload, implicated in numerous diseases, including age-related macular degeneration, induces retinal cell death via the NLRP3 inflammasome. Gelfand et al. show that iron-induced inflammasome activation depends upon accumulation of non-coding SINE RNAs (. Alu and B2 RNAs), which accrete due to impaired DICER1 processing.

Original languageEnglish
Pages (from-to)1686-1693
Number of pages8
JournalCell Reports
Volume11
Issue number11
DOIs
StatePublished - Jun 23 2015

Bibliographical note

Funding Information:
Vector to express recombinant human PCBP2 was provided by Dr. Peng Jin (Emory University). L. Toll, G.R. Pattison, R. King, L. Xu, M. McConnell, C. Payne, D. Robertson, and G. Botzet provided technical assistance. B.D.G. was supported by American Heart Association and International Retinal Research Foundation (IRRF); T.Y. was supported by Fight for Sight postdoctoral award; 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, Foundation Fighting Blindness Individual Investigator Research Award, Harrington Discovery Institute Scholar-Innovator Award, Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and Research to Prevent Blindness departmental unrestricted grant; B.J.F. was supported by NIH T32HL091812 and UL1RR033173; 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) and Bayer Global Ophthalmology Research Award; Y.K. was supported by Alcon Japan Research award; N.K. was supported by Beckman Initiative for Macular Research and NIH K99EY024336; and C.B.W. was supported by The Loris and David Rich Postdoctoral Scholar Award (IRRF). J.A. and B.J.F. are named as inventors on patent applications relating to the treatment of macular degeneration filed by their employer, the University of Kentucky. J.A. is a co-founder of iVeena (Holdings, Pharma, Delivery), which has licensed some of this technology from the University of Kentucky. J.A. has received honoraria from Allergan.

Publisher Copyright:
© 2015 The Authors.

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)

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