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

被引：224

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

共 81 条

[1] Lipofuscin Redistribution and Loss Accompanied by Cytoskeletal Stress in Retinal Pigment Epithelium of Eyes With Age-Related Macular Degeneration
Ach, Thomas
Tolstik, Elen
Messinger, Jeffrey D.
Zarubina, Anna V.
Heintzmann, Rainer
Curcio, Christine A.
[J]. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2015, 56 (05) : 3242 - 3252
[2] GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes
Aglietti, Robin A.
Estevez, Alberto
Gupta, Aaron
Ramirez, Monica Gonzalez
Liu, Peter S.
Kayagaki, Nobuhiko
Ciferri, Claudio
Dixit, Vishva M.
Dueber, Erin C.
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2016, 113 (28) : 7858 - 7863
[3] Age-related macular degeneration: Etiology, pathogenesis, and therapeutic strategies
Ambati, J
Ambati, BK
Yoo, SH
Ianchulev, S
Adamis, AP
[J]. SURVEY OF OPHTHALMOLOGY, 2003, 48 (03) : 257 - 293
[4] Immunology of age-related macular degeneration
Ambati, Jayakrishna
Atkinson, John P.
Gelfand, Bradley D.
[J]. NATURE REVIEWS IMMUNOLOGY, 2013, 13 (06) : 438 - 451
[5] Mechanisms of Age-Related Macular Degeneration
Ambati, Jayakrishna
Fowler, Benjamin J.
[J]. NEURON, 2012, 75 (01) : 26 - 39
[6] A2E Induces IL-1β Production in Retinal Pigment Epithelial Cells via the NLRP3 Inflammasome
Anderson, Owen A.
Finkelstein, Arthur
Shima, David T.
[J]. PLOS ONE, 2013, 8 (06):
[7] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death
Baines, CP
Kaiser, RA
Purcell, NH
Blair, NS
Osinska, H
Hambleton, MA
Brunskill, EW
Sayen, MR
Gottlieb, RA
Dorn, GW
Robbins, J
Molkentin, JD
[J]. NATURE, 2005, 434 (7033) : 658 - 662
[8] Rapid identification of unknown heteroplasmic mutations across the entire human mitochondrial genome with mismatch-specific Surveyor Nuclease
Bannwarth, Sylvie
Procaccio, Vincent
Paquis-Flucklinger, Veronique
[J]. NATURE PROTOCOLS, 2006, 1 (04) : 2037 - 2047
[9] Active Alu retrotransposons in the human genome
Bennett, E. Andrew
Keller, Heiko
Mills, Ryan E.
Schmidt, Steffen
Moran, John V.
Weichenrieder, Oliver
Devine, Scott E.
[J]. GENOME RESEARCH, 2008, 18 (12) : 1875 - 1883
[10] Comprehensive analysis of mitochondrial permeability transition pore activity in living cells using fluorescence-imaging-based techniques
Bonora, Massimo
Morganti, Claudia
Morciano, Giampaolo
Giorgi, Carlotta
Wieckowski, Mariusz R.
Pinton, Paolo
[J]. NATURE PROTOCOLS, 2016, 11 (06) : 1067 - 1080

← 1 2 3 4 5 6 7 8 9 →