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

Authors

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

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.

Document Type

Article

Publication Date

6-23-2015

Notes/Citation Information

Published in Cell Reports, v. 11, issue 11, p. 1686-1693.

© 2015 The Authors

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Digital Object Identifier (DOI)

http://dx.doi.org/10.1016/j.celrep.2015.05.023

Repository Citation

Gelfand, Bradley D.; Wright, Charles B.; Kim, Younghee; Yasuma, Tetsuhiro; Yasuma, Reo; Li, Shengjian; Fowler, Benjamin J.; Bastos-Carvalho, Ana; Kerur, Nagaraj; Uittenbogaard, Annette; Han, Youn Seon; Lou, Dingyuan; Kleinman, Mark E.; McDonald, W. Hayes; Núñez, Gabriel; Georgel, Philippe; Dunaief, Joshua L.; and Ambati, Jayakrishna, "Iron Toxicity in the Retina Requires Alu RNA and the NLRP3 Inflammasome" (2015). Ophthalmology and Visual Science Faculty Publications. 9.
https://uknowledge.uky.edu/ophthalmology_facpub/9