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Nat Med. 2018 Jan;24(1):50-61. doi: 10.1038/nm.4450. Epub 2017 Nov 27.

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

Author information

1
Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
2
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
3
Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA.
4
Department of Ophthalmology, University of Tsukuba, Ibaraki, Japan.
5
Doheny Eye Institute, Los Angeles, Los Angeles, California, USA.
6
Department of Ophthalmology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA.
7
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
8
Department of Ophthalmology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
9
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
10
Center for Digital Image Evaluation, Charlottesville, Virginia, USA.
11
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
12
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, USA.
13
Departments of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
14
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
15
Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, USA.
16
Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
17
Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.
18
Department of Urology, Wakayama Medical University, Wakayama, Japan.
19
Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, USA.
20
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
21
Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
22
Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
23
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Abstract

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-β production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-β, 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.

PMID:
29176737
PMCID:
PMC5760363
DOI:
10.1038/nm.4450
[Indexed for MEDLINE]
Free PMC Article

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