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

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• 作者：Valeria Tarallo¹ ; ¹⁶ ; Yoshio Hirano¹ ; ¹⁶ ; Bradley  ; D. Gelfand¹ ; ¹⁶ ; Sami Dridi¹ ; Nagaraj Kerur¹ ; Younghee Kim¹ ; Won  ; Gil Cho¹ ; ³ ; Hiroki Kaneko¹ ; Benjamin  ; J. Fowler¹ ; ² ; Sasha Bogdanovich¹ ; Romulo  ; J.C. Albuquerque¹ ; William  ; W. Hauswirth⁴ ; Vince  ; A. Chiodo⁴ ; Jennifer  ; F. Kugel⁵ ; James  ; A. Goodrich⁵ ; Steven  ; L. Ponicsan⁵ ; Gautam Chaudhuri⁶ ; Michael  ; P. Murphy⁷ ; Joshua  ; L. Dunaief⁸ ; Balamurali  ; K. Ambati⁹ ; ¹⁰ ; Yuichiro Ogura¹¹ ; Jae  ; Wook Yoo¹² ; Dong-ki Lee¹² ; Patrick Provost¹³ ; David  ; R. Hinton¹⁴ ; Gabriel Nú ; ñ ; ez¹⁵ ; Judit  ; Z. Baffi¹ ; Mark  ; E. Kleinman¹ ; Jayakrishna Ambati¹ ; ² ; ^{jamba2@email.uky.edu}
• 刊名：Cell
• 出版年：2012
• 期刊代码：50_00928674
• 类别：med
• 出版时间：11 May, 2012
• 卷：149
• 期：4
• 页码：847-859
• 文件大小：2809 K

摘要

| Figures/TablesFigures/Tables | ReferencesReferencesml version="1.0" encoding="UTF-8"?><h3 class="h3">Summaryh3>m>Alum> RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of聽age-related macular degeneration that causes blindness in millions of individuals. The mechanism of m>Alum> RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or m>Alum> RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the聽RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or m>Alum> 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.