ArticleNature medicine2018
cGAS drives noncanonical-inflammasome activation in age-related macular degeneration.
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Article in Nature medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 180 papers, 1 of them a synthesis that pooled it.
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180citing papers in PubMed, 1 pooled it
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Who cites it
180 citing papers in PubMed, 1 synthesis or guideline pooled it, 289 citations in OpenAlex.
- Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development.Nature communications · 2020Pooled it
- The Oxidative-Mitochondrial-Inflammatory Axis in Retinitis Pigmentosa: Extracellular mtDNA as Biomarker and Therapeutic Read-Out.Antioxidants (Basel, Switzerland) · 2026Review
- The cGAS-STING pathway in inflammaging and neuroinflammation.Science China. Life sciences · 2026Review
- Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer's disease brain.Cell chemical biology · 2026Article
- Targeting the cGAS-STING pathway mitigates Huntington disease pathogenesis in a knock-in mouse model.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mitochondrial Dysfunction and Oxidative Stress in Retinal Degeneration: Mechanisms, Biomarkers, and Therapeutic Perspectives.Current issues in molecular biology · 2026Review
- A multi-omics analysis of human fibroblasts overexpressing an Alu transposon reveals widespread disruptions in aging-associated pathways.GeroScience · 2026Article
- Melatonin alleviates neuroinflammation in ischemic stroke by regulating cyclic GMP-AMP synthase- mediated microglial pyroptosis signaling.Neural regeneration research · 2026Article
- The Role and Mechanism of the cGAS-STING/NLRP3 Signaling Axis-Regulated p38 MAPK/NF-κB Pathway in Manganese-Induced Tau Aggregation-Mediated Neurotoxicity.Environment & health (Washington, D.C.) · 2026Article
- DAMP signaling networks: from receptors to diverse pathophysiological functions.Journal of advanced research · 2026Review
- Development of Intervertebral Disc Organoids through Directed Differentiation of Mesenchymal Stem Cells and Hierarchical 3D Printing.ACS nano · 2026Article
- Prasugrel inhibits TLR7-driven autoimmunity in systemic lupus erythematosus by acetylating cGAS.Nature communications · 2026Article
- Permeable nanoreactor eye drop for enzymatic cascade-mediated treatment for acute retinal injury model mimicking geographic atrophy.Nature communications · 2026Article
- cGAS knockout inhibited endotoxin-induced uveitis in mice.Genes & diseases · 2026Article
- Article
- TREM2 in age-related macular degeneration: a microglia-centered perspective in the retinal myeloid landscape.Frontiers in ophthalmology · 2026Review
- Mitochondrial metabolic dysfunction drives PANoptosis in retinal pigment epithelium during fungal endophthalmitis: emerging roles of the MITF-FBXW7 axis.Frontiers in immunology · 2026Review
- The role of NLRP3 inflammasome in age-related macular degeneration: mechanisms and therapeutic prospects.Frontiers in aging neuroscience · 2026Review
- Excessive Kynurenine Metabolism Impairs Lysosomal acidification and Triggers mtDNA Release via the AHR/CISH/ATP6V1A Axis in Decidual Macrophages Associated with Unexplained Recurrent Pregnancy Loss.International journal of biological sciences · 2026Article
- Targeting Ash1L-STING Axis Restores NK Cell Function and Ameliorates Immune-Mediated Bone Marrow Failure Diseases.International journal of biological sciences · 2026Article
120 more citing papers are in PubMed but not listed here.
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Authors and funding
38 authors at 17 institutions in 2 countries.
Nagaraj KerurCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.ORCID 0000-0001-5040-2129
Shinichi FukudaCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.ORCID 0000-0002-4160-8229
Daipayan BanerjeeCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Younghee KimCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Dongxu FuCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Ivana ApicellaCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Akhil VarshneyCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Reo YasumaCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Benjamin J FowlerDepartment of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA.
Elmira BaghdasaryanDoheny Eye Institute, Los Angeles, Los Angeles, California, USA.
Kenneth M MarionDoheny Eye Institute, Los Angeles, Los Angeles, California, USA.ORCID 0000-0003-1275-5729
Xiwen HuangDoheny Eye Institute, Los Angeles, Los Angeles, California, USA.ORCID 0000-0003-2174-1767
Tetsuhiro YasumaDepartment of Ophthalmology, University of Tsukuba, Ibaraki, Japan.
Yoshio HiranoDepartment of Ophthalmology, University of Tsukuba, Ibaraki, Japan.ORCID 0000-0002-9173-0839
Vlad SerbuleaDepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Meenakshi AmbatiCenter for Digital Image Evaluation, Charlottesville, Virginia, USA.
Vidya L AmbatiCenter for Digital Image Evaluation, Charlottesville, Virginia, USA.
Yuji KajiwaraDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.ORCID 0000-0002-9307-8215
Kameshwari AmbatiCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Shuichiro HiraharaCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Ana Bastos-CarvalhoDepartment of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA.
Yuichiro OguraDepartment of Ophthalmology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Hiroko TerasakiDepartment of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Tetsuro OshikaDepartment of Ophthalmology, University of Tsukuba, Ibaraki, Japan.
Kyung Bo KimDepartment of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, USA.
David R HintonDepartments of Pathology and Ophthalmology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Norbert LeitingerDepartment of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
John C CambierDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Joseph D BuxbaumDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
M Cristina KenneyGavin Herbert Eye Institute, University of California Irvine, Irvine, California, USA.
S Michal JazwinskiTulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
Hiroshi NagaiDivision of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.ORCID 0000-0002-3779-9085
Isao HaraDepartment of Urology, Wakayama Medical University, Wakayama, Japan.
A Phillip WestDepartment of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, USA.
Katherine A FitzgeraldDivision of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
SriniVas R SaddaDoheny Eye Institute, Los Angeles, Los Angeles, California, USA.
Bradley D GelfandCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Jayakrishna AmbatiCenter for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA.ORCID 0000-0003-1622-6365
University of Kentucky · USUniversity of Virginia · USUniversity of Tsukuba · JPCenter for Digital Image Evaluation · USDoheny Eye Institute · USIcahn School of Medicine at Mount Sinai · USUniversity of California, Los Angeles · USKobe University · JPNagoya City University · JPNagoya University · JPTexas A&M University · USTulane University · USUniversity of California, Irvine · USUniversity of Colorado Denver · USUniversity of Massachusetts Chan Medical School · USUniversity of Southern California · USWakayama Medical University · JP
Funding
Role of Pannexins in Vascular Smooth Muscle CellsP01HL120840 · NHLBI · UNIVERSITY OF VIRGINIA · PI RAVICHANDRAN, KODI S · 2014 to 2023
$24.0MKentucky Center for Clinical and Translational ScienceUL1TR000117 · NCATS · UNIVERSITY OF KENTUCKY · PI KERN, PHILIP A · 2012 to 2015
$13.3MTRAINING IN THE PHARMACOLOGICAL SCIENCEST32GM007055 · NIGMS · UNIVERSITY OF VIRGINIA CHARLOTTESVILLE · PI LYNCH, KEVIN R. · 1985 to 2022
$7.2MEXPERIMENTAL APPROACH TO MACULOPATHYR01EY001545 · NEI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HINTON, DAVID R. · 1985 to 2016
$6.0MCELLULAR AGING IN A YEAST MODEL SYSTEMR37AG006168 · NIA · TULANE UNIVERSITY OF LOUISIANA · PI JAZWINSKI, S MICHAL · 1994 to 2016
$5.0MGene Regulation in Innate ImmunityR37AI067497 · NIAID · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI FITZGERALD, KATHERINE A. · 2015 to 2024
$4.6MForm and function of our Janus faced genomeDP1GM114862 · NIGMS · UNIVERSITY OF VIRGINIA · PI AMBATI, JAYAKRISHNA · 2014 to 2018
$4.0MKENTUCKY CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCEUL1RR033173 · NCRR · UNIVERSITY OF KENTUCKY · PI KERN, PHILIP A · 2011 to 2011
$3.5MFunctional studies of DICER1 and Alu RNA in geographic atrophyR01EY022238 · NEI · UNIVERSITY OF VIRGINIA · PI AMBATI, JAYAKRISHNA · 2012 to 2016
$3.3MInflammasome Activation in Geographic AtrophyR01EY024068 · NEI · UNIVERSITY OF VIRGINIA · PI AMBATI, JAYAKRISHNA · 2014 to 2017
$2.6MAutoimmunity risk alleles compromising B cell anergyR01AI124487 · NIAID · UNIVERSITY OF COLORADO DENVER · PI CAMBIER, JOHN C · 2016 to 2020
$2.5MClinical Scholars In Cardiovascular ScienceT32HL091812 · NHLBI · UNIVERSITY OF KENTUCKY · PI SMYTH, SUSAN S. · 2008 to 2018
$2.3MNCATS NIH HHS UL1 TR000117NCRR NIH HHS UL1 RR033173NEI NIH HHS K99 EY024336NEI NIH HHS R00 EY024336NEI NIH HHS R01 EY001545NEI NIH HHS R01 EY018350NEI NIH HHS R01 EY018836NEI NIH HHS R01 EY020672NEI NIH HHS R01 EY022238NEI NIH HHS R01 EY024068NHLBI NIH HHS P01 HL120840NHLBI NIH HHS T32 HL091812NIAID NIH HHS R01 AI124487NIAID NIH HHS R21 AI099346NIAID NIH HHS R37 AI067497NIA NIH HHS R37 AG006168NIDDK NIH HHS F31 DK108553NIDDK NIH HHS R01 DK096076NIGMS NIH HHS DP1 GM114862NIGMS NIH HHS T32 GM007055
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.
Indexed as
AnimalsCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseDEAD-box RNA HelicasesGeographic AtrophyHumansInflammasomesInterferon Type IMiceNucleotidyltransferasesRetinal Pigment EpitheliumRibonuclease IIISignal TransductioncGAS protein, humanCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseDEAD-box RNA HelicasesDICER1 protein, humanInflammasomesInterferon Type INucleotidyltransferasesRibonuclease III
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