DICER1 Loss and Alu RNA Induce Age-Related Macular Degeneration via the NLRP3 Inflammasome and MyD88

• Published in: Cell 2012-05, Vol.149 (4), p.847-859
• Main Authors: Tarallo, Valeria, Hirano, Yoshio, Gelfand, Bradley D., Dridi, Sami, Kerur, Nagaraj, Kim, Younghee, Cho, Won Gil, Kaneko, Hiroki, Fowler, Benjamin J., Bogdanovich, Sasha, Albuquerque, Romulo J.C., Hauswirth, William W., Chiodo, Vince A., Kugel, Jennifer F., Goodrich, James A., Ponicsan, Steven L., Chaudhuri, Gautam, Murphy, Michael P., Dunaief, Joshua L., Ambati, Balamurali K., Ogura, Yuichiro, Yoo, Jae Wook, Lee, Dong-ki, Provost, Patrick, Hinton, David R., Núñez, Gabriel, Baffi, Judit Z., Kleinman, Mark E., Ambati, Jayakrishna
• Format: Article
• Language: English
• Subjects: Alu Elements; Animals; atrophy; blindness; Carrier Proteins - metabolism; caspase-1; cytotoxicity; DEAD-box RNA Helicases - metabolism; epithelium; Geographic Atrophy - immunology; Geographic Atrophy - metabolism; Geographic Atrophy - pathology; Humans; immune system; immunomodulation; Inflammasomes - immunology; Inflammasomes - metabolism; interleukin-18; macular degeneration; Mice; Myeloid Differentiation Factor 88 - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Ribonuclease III - metabolism; RNA; Toll-Like Receptors - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.03.036

Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that 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. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements. [Display omitted] ► Alu RNA accumulation due to DICER1 deficiency activates NLRP3 inflammasome in RPE ► Pharmacological inhibition of the inflammasome, MyD88, or IL18 prevents degeneration ► Alu RNA induced RPE degeneration via mitochondrial ROS production, IL18, and MyD88 ► RPE in human geographic atrophy eyes display evidence of NLRP3 and MyD88 activation Age-related macular degeneration (AMD) is an untreatable form of blindness caused by cell death in the retina. In AMD, the accumulation of Alu RNAs trigger cell death by activating the NLRP3 inflammasome; blocking these pathways pharmacologically prevents degeneration.