Roles of sting in a lupus mouse model of Fcgr2b-deficient mice

Abstract

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease causing the immunological abnormalities leads to the production of autoantibodies, immune complex deposition and inflammatory cytokines that affect multiple organs. Type I interferon has been shown as one of the most crucial cytokines involving in the pathogenesis of autoimmune diseases such as SLE. Activation via nucleic acid sensors can induce the production of type I interferon from dendritic cells and promote SLE severity. Stimulator of interferon genes (Sting) is a cytoplasmic DNA sensor that signals downstream to enhance type I interferon production after its activation. Recently, it was shown that a gain mutation in the STING gene resulting in over-activity of the IFN pathway can cause familial inflammatory syndrome with lupus-like manifestations in humans. However, the functional studies of Sting in different autoimmune mouse models suggest the conflicting roles of Sting in the pathogenesis of autoimmune diseases. In order to determine if Sting participates in lupus pathogenesis, the Fcgr2b-deficienct mice (lupus mouse model) were bred with Sting-deficient mice to create the double-deficient mice. All mice were determined the disease phenotypes. The results show that in the absence of Sting, the Fcgr2b-deficient mice do not develop fatal glomerulonephritis and autoantibodies. Sting signaling promoted the dendritic cell maturation and the plasmacytoid dendritic cell differentiation. After Sting activation, Sting was phosphorylated, and Lyn was recruited to interact with Sting. The adoptive transfer of Sting-activated bone marrow-derived dendritic cells (BMDC) into the double-deficient mice restored the lupus phenotypes.The original knowledge from this study is a proof of concept for targeting Sting as a future promising treatment in autoimmune diseases.