Distinct Effect of Type III Interferon on Trex1KO autoimmune model 2307705

Introduction The Tree-prime Repair Exonuclease 1 (Trex1) is a 3’→5’ exonuclease that degrades cytosolic nucleic acids. Mutations in Trex1 are associated with a broad spectrum of autoimmune diseases, such as AGS and SLE. Trex1 deficiency leads to accumulation of cytosolic self-DNA, which induces hyper-activation of the immune system including systemic inflammation, auto-antibody production, and tissue damage. Type I IFN responses in Trex1 deficiency models have been well-studied. However, the function of type III interferon is incompletely understood. Methods We generated Ifnlr1KO and cGASKO mice on the genetic background of Trex1KO mice. Results In our studies, we found that MNoV infection is prevented in Trex1-/- mice but not in Trex1-/-cGAS-/- and Trex1-/-Ifnlr1-/- mice. This indicates that the type III interferon signaling pathway activated in the intestine of Trex1-/- mice is dependent on cGAS-STING. In addition, Trex1-/-Ifnlr1-/- partially alleviates the upregulation of retroelements and the induction of robust interferon stimulated genes (ISG) in intestinal tissues from Trex1-/- mice. Furthermore, the production of auto-antibodies and subsequent tissue damage seen in Trex1-/- mice is alleviated in Trex1-/-Ifnlr1-/- mice. These ameliorations from the loss of Ifnlr1 rescues the survival of Trex1-/- mice. Conclusion We conclude that the accumulation of mislocated nucleic acids activates type III interferon signaling through cGAS-STING in Trex1-/- mice. The type III interferon signaling activation protects the mice from MNoV infection but contributes to hyperinflammation and auto-antibody production, which accelerates tissue damage and increases mortality in Trex1-/- mice. Since interferon lambda receptor’s expression is restricted to gut epithelial cells, it implies the local intestine plays a complex role in exacerbating systemic inflammation in the auto-immune disease model. Blockage of type III interferon signaling might be a therapeutic target for attenuating the symptoms of autoimmune Funding Source NIH Topic Categories Basic Autoimmunity (BA)