cGAS drives noncanonical-inflammasome activation in age-related macular degeneration

被引：232

作者：

Kerur, Nagaraj ^{[1
,2
,3
]}

Fukuda, Shinichi ^{[1
,2
,4
]}

Banerjee, Daipayan ^{[1
,2
,3
]}

Kim, Younghee ^{[1
,2
,3
]}

Fu, Dongxu ^{[1
,2
]}

Apicella, Ivana ^{[1
,2
]}

Varshney, Akhil ^{[1
,2
]}

Yasuma, Reo ^{[1
,2
,3
]}

Fowler, Benjamin J. ^{[3
]}

Baghdasaryan, Elmira ^{[5
,6
]}

Marion, Kenneth M. ^{[5
]}

Huang, Xiwen ^{[5
]}

Yasuma, Tetsuhiro ^{[4
,7
]}

Hirano, Yoshio ^{[4
,8
]}

Serbulea, Vlad ^{[9
]}

Ambati, Meenakshi ^{[10
]}

Ambati, Vidya L. ^{[10
]}

Kajiwara, Yuji ^{[11
]}

Ambati, Kameshwari ^{[1
,2
,3
]}

Hirahara, Shuichiro ^{[1
,2
]}

Bastos-Carvalho, Ana ^{[3
]}

Ogura, Yuichiro ^{[8
]}

Terasaki, Hiroko ^{[7
]}

Oshika, Tetsuro ^{[4
]}

Kim, Kyung Bo ^{[12
]}

Hinton, David R. ^{[13
,14
]}

Leitinger, Norbert ^{[9
]}

Cambier, John C. ^{[15
]}

Buxbaum, Joseph D. ^{[11
]}

Kenney, M. Cristina ^{[16
]}

Jazwinski, S. Michal ^{[17
,18
]}

Nagai, Hiroshi ^{[19
]}

Hara, Isao ^{[20
]}

West, A. Phillip ^{[21
]}

Fitzgerald, Katherine A. ^{[22
]}

Sadda, SriniVas R. ^{[5
,6
]}

Gelfand, Bradley D. ^{[1
,2
,3
,23
]}

Ambati, Jayakrishna ^{[1
,2
,3
,24
,25
]}

机构：

[1] Univ Virginia, Sch Med, Ctr Adv Vis Sci, Charlottesville, VA 22908 USA

[2] Univ Virginia, Sch Med, Dept Ophthalmol, Charlottesville, VA 22908 USA

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

[4] Univ Tsukuba, Dept Ophthalmol, Ibaraki, Japan

[5] Doheny Eye Inst, 1355 San Pablo St, Los Angeles, CA 90033 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA

[7] Nagoya Univ, Dept Ophthalmol, Grad Sch Med, Nagoya, Aichi, Japan

[8] Nagoya City Univ, Dept Ophthalmol, Grad Sch Med Sci, Nagoya, Aichi, Japan

[9] Univ Virginia, Sch Med, Dept Pharmacol, Charlottesville, VA 22908 USA

[10] Ctr Digital Image Evaluat, Charlottesville, VA USA

[11] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[12] Univ Kentucky, Dept Pharmaceut Sci, Lexington, KY USA

[13] Univ Southern Calif, Keck Sch Med, USC Roski Eye Inst, Dept Pathol, Los Angeles, CA USA

[14] Univ Southern Calif, Keck Sch Med, USC Roski Eye Inst, Dept Ophthalmol, Los Angeles, CA USA

[15] Univ Colorado, Sch Med, Dept Immunol & Microbiol, Aurora, CO USA

[16] Univ Calif Irvine, Gavin Herbert Eye Inst, Irvine, CA USA

[17] Tulane Univ, Tulane Ctr Aging, Hlth Sci Ctr, New Orleans, LA 70118 USA

[18] Tulane Univ, Dept Med, Hlth Sci Ctr, New Orleans, LA 70118 USA

[19] Kobe Univ, Grad Sch Med, Dept Internal Related, Div Dermatol, Kobe, Hyogo, Japan

[20] Wakayama Med Univ, Dept Urol, Wakayama, Japan

[21] Texas A&M Univ, Dept Microbial Pathogenesis & Immunol, College Stn, TX USA

[22] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA USA

[23] Univ Virginia, Sch Med, Dept Biomed Engn, Charlottesville, VA 22908 USA

[24] Univ Virginia, Sch Med, Dept Pathol, Charlottesville, VA 22908 USA

[25] Univ Virginia, Sch Med, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA

来源：

NATURE MEDICINE | 2018年 / 24卷 / 01期

基金：

美国国家卫生研究院;

关键词：

MITOCHONDRIAL PERMEABILITY TRANSITION; RETINAL-PIGMENT EPITHELIUM; INNATE IMMUNE-RESPONSES; NLRP3; INFLAMMASOME; CELL-DEATH; ALU RNA; OXIDIZED PHOSPHOLIPIDS; CORNEAL ENDOTHELIUM; GENE-EXPRESSION; ARPE-19; CELLS;

D O I：

10.1038/nm.4450

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)dependent interferon-b production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or AluRNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-b, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.

引用

页码：50 / +

页数：16

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