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

J Immunol. 2015 Sep 1;195(5):1939-43. doi: 10.4049/jimmunol.1500969. Epub 2015 Jul 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Autoantibodies
  • Nucleotides, Cyclic
  • Phosphoproteins
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Interferon-beta
  • Interferons
  • Nucleotidyltransferases
  • cGAS protein, mouse
  • Exodeoxyribonucleases
  • three prime repair exonuclease 1

Supplementary concepts

  • Aicardi-Goutieres syndrome