postdoc Brown University Providence, Rhode Island, United States
Disclosure(s):
Li Zhang, PhD: No financial relationships to disclose
Introduction/Rationale: 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
