Diced Alu: Canning the blinding inflammasome

Abstract

AbstractPurpose To determine the mechanisms of retinal pigmented epithelium (RPE) cell death induced by DICER1 deficient and Alu RNA accumulation, which are observed in human geographic atrophy RPE.Methods Human and mouse RPE cell culture studies were combined with in vivo mouse models of RPE degeneration induced by DICER1 targeting or Alu RNA exposure.Results DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR‐independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase‐1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. Human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase‐1 and MyD88 activation.Conclusion These findings provide a rationale for targeting the NLRP3 inflammasome and IL18/MyD88 pathways in GA. Commercial interest