Journal
JOURNAL OF IMMUNOLOGY
Volume 195, Issue 5, Pages 1939-1943Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1500969
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Funding
- National Institutes of Health [AI084914]
- Cancer Research Institute Irvington postdoctoral fellowship
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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-Goutieres 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-Goutieres syndrome and related autoimmune diseases.
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