Inhibition of Sting rescues lupus disease by the regulation of Lyn-mediated dendritic cell differentiation

Abstract

AbstractSLE (systemic lupus erythematosus) is an autoimmune disease that causes chronic inflammation and leads to fatality if left untreated. Immune complex-mediated inflammation and type I IFN signaling pathways are one of the mechanisms initiating lupus disease. Signaling through stimulator of interferon genes (STING) leads to the production of type I IFN and inflammatory cytokines. However, the role of STING in lupus mouse models is controversy. Here we demonstrated the mechanisms of STING involving in SLE pathogenesis at the molecular level. The disruption of STING signaling rescued lupus disease inFcgr2b-deficient mice. STING activated DC facilitated T cell proliferation, which depended on intrinsic expression of STING on DC but not on T cells. Upon STING activation, LYN was recruited and co-localized with STING in bone marrow-derived dendritic cells (BMDC). STING signaling induced phosphorylated LYN and AKT. The inhibition of LYN prohibited STING-induced DC differentiation. Adoptive transfer of STING-activated BMDC into the FCGR2B and STING double-deficiency mice restored lupus phenotypes. These findings provide the proof of concept that inhibition of STING signaling is a promising therapeutic approach for SLE patients.