Abstract
Abstract Patients defective in the 3’ repair exonuclease 1 (Trex1) suffer from Aicardi-Goutieres Syndrome (AGS) which instigates lethal encephalitis characterized by high levels of type I IFN production being present in the cerebrospinal fluid. Trex1 deficient mice exhibit a median life span of approximately 9 weeks since as yet uncharacterized self-DNA, presumably normally digested by Trex1, activates intracellular DNA sensors which triggers cytokine production and causes lethal inflammatory aggravated myocarditis. STING is essential for triggering cytoplasmic DNA-dependent innate immune signaling that comprises the production of type I IFN. Loss of TREX1 was observed to augment ssDNA and dsDNA-mediated induction of type I IFN in a STING-dependent manner. The replication of HSV1 was greatly reduced in hTERT-BJ1 or MEF lacking TREX1 due to elevated STING-dependent cytokine production. Loss of STING was observed to significantly extend the lifespan of Trex1-/- due to prevention of myocarditis. Microarray analysis showed dramatically reduced levels of proinflammatory genes in the hearts of Sting-/- Trex1-/-, Sting-/+ Trex1-/- compared to Trex1-/- mice. Anti-nuclear autoantibody (ANA) observed to be highly prevalent in the sera of Trex1-/- mice was almost completely absent in the sera of Sting-/- Trex1-/- mice. These data indicates that STING is responsible for pro-inflammatory gene induction in Trex1 deficient mice and plausibly may be involved in AGS.
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