The induction of type I interferonopathy in Trex1-P212fs mice is mediated by activation of the cGAS-STING pathway

The cGAS-STING pathway is crucial for immune tolerance, pathogen resistance, and tumor immunity. Knocking out the cGAS gene can reverse the type I interferonopathy seen in Trex1^-/- and Trex1^D18N/D18N mice. TREX1, a key DNA-specific exonuclease in mammalian cells, degrades cytoplasmic DNA to prevent excessive immune activation. Mutations in TREX1 are linked to various autoimmune diseases. In prior research, we generated a Trex1-P212fs mouse model associated with systemic lupus erythematosus (SLE) using CRISPR-Cas9 gene editing. This model displays systemic inflammation that mirrors numerous characteristics of both Aicardi-Goutières syndrome (AGS) and SLE in humans. In this study, we found that the TREX1-P212fs mutation resulted in reduced dsDNA enzyme activity. DNA accumulation was present in the cytoplasm of Trex1^{P212fs/P212fs} MEFs. Nonetheless, the role of the cGAS-STING pathway in mediating the disease phenotype in Trex1-P212fs mice associated with SLE has yet to be elucidated. We observed that cGas knockout mitigated systemic inflammation, lymphocyte proliferation, vasculitis, renal disease, and spontaneous T cell activation in Trex1-P212fs mice. Similarly, inhibition of STING with C-176 treatment ameliorated the disease phenotype in Trex1-P212fs mice. These findings elucidate the pathogenesis of TREX1-P212fs-associated type I interferonopathy and offer potential therapeutic targets for their treatment.