title: Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi-Goutières Syndrome.
abstract: 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.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195;
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gray
authors.affiliation: Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA 98195;
authors.forename: Piper M
authors.initials: PM
authors.lastname: Treuting
authors.affiliation: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195; and Department of Bioengineering, University of Washington School of Medicine, Seattle, WA 98195.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Woodward
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195; stetson@uw.edu.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Stetson
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000166:cytology; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007372:Interferons / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009421:Nervous System Malformations / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009712:Nucleotides, Cyclic / Q000276:immunology / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D001323:Autoantibodies; D005090:Exodeoxyribonucleases; D016899:Interferon-beta; D007372:Interferons; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D010750:Phosphoproteins; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C429526:three prime repair exonuclease 1