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

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