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

被引：542

作者：

Tarallo, Valeria ^{[1
]}

Hirano, Yoshio ^{[1
]}

Gelfand, Bradley D. ^{[1
]}

Dridi, Sami ^{[1
]}

Kerur, Nagaraj ^{[1
]}

Kim, Younghee ^{[1
]}

Cho, Won Gil ^{[1
,3
]}

Kaneko, Hiroki ^{[1
]}

Fowler, Benjamin J. ^{[1
,2
]}

Bogdanovich, Sasha ^{[1
]}

Albuquerque, Romulo J. C. ^{[1
]}

Hauswirth, William W. ^{[4
]}

Chiodo, Vince A. ^{[4
]}

Kugel, Jennifer F. ^{[5
]}

Goodrich, James A. ^{[5
]}

Ponicsan, Steven L. ^{[5
]}

Chaudhuri, Gautam ^{[6
]}

Murphy, Michael P. ^{[7
]}

Dunaief, Joshua L. ^{[8
]}

Ambati, Balamurali K. ^{[9
,10
]}

Ogura, Yuichiro ^{[11
]}

Yoo, Jae Wook ^{[12
,13
,14
]}

Lee, Dong-ki ^{[12
,13
,14
]}

Provost, Patrick ^{[15
,16
]}

Hinton, David R. ^{[17
]}

Nunez, Gabriel ^{[18
,19
]}

Baffi, Judit Z. ^{[1
]}

Kleinman, Mark E. ^{[1
]}

Ambati, Jayakrishna ^{[1
,2
]}

机构：

[1] Univ Kentucky, Dept Ophthalmol & Visual Sci, Lexington, KY 40506 USA

[2] Univ Kentucky, Dept Physiol, Lexington, KY 40506 USA

[3] Yonsei Univ, Wonju Coll Med, Dept Anat, Wonju 220701, South Korea

[4] Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA

[5] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA

[6] Meharry Med Coll, Dept Microbiol & Immunol, Nashville, TN 37208 USA

[7] MRC, Mitochondrial Biol Unit, Cambridge CB2 0XY, England

[8] Univ Penn, Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA

[9] Univ Utah, Sch Med, Moran Eye Ctr, Dept Ophthalmol & Visual Sci, Salt Lake City, UT 84132 USA

[10] Vet Affairs Salt Lake City Healthcare Syst, Dept Ophthalmol, Salt Lake City, UT 84148 USA

[11] Nagoya City Univ, Grad Sch Med Sci, Dept Ophthalmol & Visual Sci, Nagoya, Aichi 4678601, Japan

[12] Sungkyunkwan Univ, Global Res Lab RNAi Med, Suwon 440746, South Korea

[13] Sungkyunkwan Univ, Sch Chem Mat Sci BK21, Suwon 440746, South Korea

[14] Sungkyunkwan Univ, Dept Chem, Suwon 440746, South Korea

[15] Univ Laval, CHUL Res Ctr, CHUQ, Quebec City, PQ G1K 7P4, Canada

[16] Univ Laval, Fac Med, Quebec City, PQ G1K 7P4, Canada

[17] Univ So Calif, Doheny Eye Inst, Arnold & Mabel Beckman Macular Res Ctr, Los Angeles, CA 90033 USA

[18] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[19] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

来源：

CELL | 2012年 / 149卷 / 04期

关键词：

RETINAL-PIGMENT EPITHELIUM; ENDOTHELIAL GROWTH-FACTOR; INNATE IMMUNE-RESPONSES; DOUBLE-STRANDED-RNA; CELL-DEATH; ACTIVATION; RECOGNITION; CASPASE-1; PROTEIN; IL-1;

D O I：

10.1016/j.cell.2012.03.036

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：847 / 859

页数：13

共 82 条

[1]

Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function [J].