title: Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA; Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40536, USA; Department of Microbiology, Immunology, and Human Genetics, University of Kentucky, Lexington, KY 40536, USA. Electronic address: brad.gelfand@uky.edu.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Gelfand
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Wright
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Younghee
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Yasuma
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Reo
authors.initials: R
authors.lastname: Yasuma
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Shengjian
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Fowler
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Bastos-Carvalho
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Nagaraj
authors.initials: N
authors.lastname: Kerur
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Uittenbogaard
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Youn Seon
authors.initials: YS
authors.lastname: Han
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Dingyuan
authors.initials: D
authors.lastname: Lou
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Kleinman
authors.affiliation: Proteomics Laboratory, Mass Spectrometry Research Center and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37205, USA.
authors.forename: W Hayes
authors.initials: WH
authors.lastname: McDonald
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
authors.affiliation: INSERM UMR_S 1109, Fédération de Médecine Translationnelle (FMTS), Université de Strasbourg, Strasbourg 67085, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Georgel
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Dunaief
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
mesh_terms: D020087:Alu Elements; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism; D007501:Iron / Q000494:pharmacology / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C501904:Pcbp2 protein, mouse; D016601:RNA-Binding Proteins; D007501:Iron; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D020170:Caspase 1; D053487:DEAD-box RNA Helicases