Chronic STING-dependent signaling in phagocytes aggravates TREX1-contingent inflammatory disease (INM2P.353)

Abstract

Abstract Patients defective in the 3’ repair exonuclease 1 (Trex1) suffer from Aicardi-Goutieres Syndrome (AGS) characterized by lethal encephalitis caused by high levels of circulating type I IFN production. Trex1-/- mice similarly suffer a short life span due to inflammatory myocarditis. Our data indicates that Trex1 is responsible for eliminating DNA species that otherwise activate STING (Stimulator of Interferon Genes), a key innate immune regulator responsible for facilitating cytosolic DNA-mediated cytokine production. Loss of STING (Trex1-/- STING-/-) was observed to dramatically extend the lifespan of Trex1-/- mice due to the prevention pro-inflammatory gene induction. However, we noted that Trex1-/- macrophages did not exhibit an augmented ability to produce cytokines following exposure to STING-dependent activators, but rather appeared chronically activated, exhibiting high basal level cytokine production. The source of STING activator was found to involve intrinsic genomic DNA left over from hematopoetic cell division processes that leaked into the cytoplasm, the elimination of which usually require Trex1. Accordingly, Trex1-manifested disease could be alleviated following adoptive transfer of normal bone marrow into Trex1-/- mice. Collectively, our data indicates that STING is responsible for pro-inflammatory gene induction induced by intrinsic self-DNA in Trex1 deficient mice and provides new insight into the molecular mechanisms underlining self-DNA-mediated disease.