1. Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome.
- Author
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Gelfand BD, Wright CB, Kim Y, Yasuma T, Yasuma R, Li S, Fowler BJ, Bastos-Carvalho A, Kerur N, Uittenbogaard A, Han YS, Lou D, Kleinman ME, McDonald WH, Núñez G, Georgel P, Dunaief JL, and Ambati J
- Subjects
- Animals, Carrier Proteins genetics, Caspase 1 genetics, Caspase 1 metabolism, DEAD-box RNA Helicases genetics, DEAD-box RNA Helicases metabolism, Inflammasomes metabolism, Iron pharmacology, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Retinal Pigment Epithelium drug effects, Ribonuclease III genetics, Ribonuclease III metabolism, Alu Elements, Carrier Proteins metabolism, Iron toxicity, Retinal Pigment Epithelium metabolism
- 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., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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