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: 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
• Journal: Cell reports (Cell Rep) Vol. 11 Issue 11 Pg. 1686-93 (Jun 23 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 26074074 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Pcbp2 protein, mouse
• RNA-Binding Proteins
• Iron
• Dicer1 protein, mouse
• Ribonuclease III
• Caspase 1
• DEAD-box RNA Helicases

Topics

• Alu Elements
• Animals
• Carrier Proteins (genetics, metabolism)
• Caspase 1 (genetics, metabolism)
• DEAD-box RNA Helicases (genetics, metabolism)
• Inflammasomes (metabolism)
• Iron (pharmacology, toxicity)
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein
• RNA-Binding Proteins (genetics, metabolism)
• Retinal Pigment Epithelium (drug effects, metabolism)
• Ribonuclease III (genetics, metabolism)