Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi–Goutières Syndrome

• Published in: The Journal of immunology (1950) Vol. 195; no. 5; pp. 1939 - 1943
• Main Authors: Gray, Elizabeth E, Treuting, Piper M, Woodward, Joshua J, Stetson, Daniel B
• Format: Journal Article
• Language: English
• Published: United States 01.09.2015
• Subjects: Animals; Autoantibodies - blood; Autoantibodies - immunology; Autoimmune Diseases of the Nervous System - genetics; Autoimmune Diseases of the Nervous System - immunology; Autoimmune Diseases of the Nervous System - metabolism; Cells, Cultured; Disease Models, Animal; Embryo, Mammalian - cytology; Exodeoxyribonucleases - genetics; Exodeoxyribonucleases - immunology; Exodeoxyribonucleases - metabolism; Fibroblasts - drug effects; Fibroblasts - immunology; Fibroblasts - metabolism; Gene Expression - drug effects; Gene Expression - immunology; Humans; Immunoblotting; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Interferon-beta - genetics; Interferon-beta - immunology; Interferon-beta - metabolism; Interferons - immunology; Interferons - pharmacology; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice, Inbred C57BL; Mice, Knockout; Nervous System Malformations - genetics; Nervous System Malformations - immunology; Nervous System Malformations - metabolism; Nucleotides, Cyclic - immunology; Nucleotides, Cyclic - metabolism; Nucleotidyltransferases - genetics; Nucleotidyltransferases - immunology; Nucleotidyltransferases - metabolism; Phosphoproteins - genetics; Phosphoproteins - immunology; Phosphoproteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1500969

Detection of intracellular DNA triggers activation of the stimulator of IFN genes–dependent IFN-stimulatory DNA (ISD) pathway, which is essential for antiviral immune responses. However, chronic activation of this pathway is implicated in autoimmunity. Mutations in TREX1, a 3′ repair exonuclease that degrades cytosolic DNA, cause Aicardi–Goutières syndrome and chilblain lupus. Trex1−/− mice develop lethal, IFN-driven autoimmune disease that is dependent on activation of the ISD pathway, but the DNA sensors that detect the endogenous DNA that accumulates in Trex1−/− mice have not been defined. Multiple DNA sensors have been proposed to activate the ISD pathway, including cyclic GMP–AMP synthase (cGAS). In this study, we show that Trex1−/− mice lacking cGAS are completely protected from lethality, exhibit dramatically reduced tissue inflammation, and fail to develop autoantibodies. These findings implicate cGAS as a key driver of autoimmune disease and suggest that cGAS inhibitors may be useful therapeutics for Aicardi–Goutières syndrome and related autoimmune diseases.