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DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88 |
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| 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 |
| Institution: | 1 Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, KY 40506, USA 2 Department of Physiology, University of Kentucky, Lexington, KY 40506, USA 3 Department of Anatomy, Yonsei University Wonju College of Medicine, Wonju City 220-701, Korea 4 Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA 5 Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309, USA 6 Department of Microbiology and Immunology, Meharry Medical College, Nashville, TN 37208, USA 7 MRC Mitochondrial Biology Unit, MRC/Wellcome Trust Building, Hills Road, Cambridge CB2 0XY, UK 8 F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA 9 Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132, USA 10 Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT 84148, USA 11 Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan 12 Global Research Laboratory for RNAi Medicine & BK21 School of Chemical Materials Science and Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea 13 CHUL Research Center/CHUQ and Faculty of Medicine, Université Laval, Quebec QC G1K 7P4, Canada 14 The Arnold and Mabel Beckman Macular Research Center at the Doheny Eye Institute, University of Southern California, Los Angeles, CA 90033, USA 15 Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA |
| Abstract: | 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. |
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