Respiratory viruses and exacerbations of asthma in adults.

TLDR

Intracellular DNA activates the ISD pathway, essential for antiviral immunity, but chronic activation drives autoimmunity, as seen in TREX1 mutations and Trex1‑/‑ mice, where the responsible DNA sensor remains undefined. Loss of cGAS in Trex1‑/‑ mice prevents lethal disease, eliminates autoantibodies, and indicates that cGAS inhibition could treat Aicardi–Goutières syndrome and related autoimmune disorders.

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 <i>TREX1</i>, a 3′ repair exonuclease that degrades cytosolic DNA, cause Aicardi–Goutières syndrome and chilblain lupus. <i>Trex1</i>^−/− 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 <i>Trex1</i>^−/− 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 <i>Trex1</i>^−/− 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.