Artigo Acesso aberto Revisado por pares

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

2015; American Association of Immunologists; Volume: 195; Issue: 5 Linguagem: Inglês

10.4049/jimmunol.1500969

ISSN

1550-6606

Autores

Elizabeth Gray, Piper M. Treuting, Joshua J. Woodward, Daniel B. Stetson,

Tópico(s)

Immune Response and Inflammation

Resumo

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.

Referência(s)