Type I Interferon-Dependent and -Independent TRIF Signaling are Required for Autoantibody Generation in an Induced Model of Systemic Lupus Erythematosus

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune condition characterized by the production of autoantibodies to cellular and nuclear self-antigens, with damage to multiple organs. Immunization with the SLE autoantigen β2-glycoprotein I (β2GPI) and TLR4 ligand lipopolysaccharide (LPS) induces a murine model of SLE characterized by the generation of autoantibodies to multiple SLE antigens. LPS induces both inflammatory cytokines and type I interferons (IFNs) by signaling through the adaptor proteins MyD88 and TRIF, respectively. We investigated the mechanisms of LPS-dependent signaling on the induction of murine SLE following β2GPI/LPS immunization. Immunization of mice deficient in MyD88 or TRIF with β2GPI/LPS revealed that LPS-dependent TRIF signaling preferentially promoted autoantibody production in this model, compared to MyD88 signaling. Furthermore, SLE-specific autoantibody production was induced by TLR3 or TLR4 agonists, in combination with β2GPI, but not by agonists of TRIF-independent TLRs. RNA-sequencing of dendritic cells and macrophages isolated from wildtype (WT) and TRIF-deficient mice immunized with β2GPI/LPS revealed differential expression of both type I IFN-dependent and -independent genes. Moreover, type I IFN receptor (IFNaR)-deficient mice immunized with β2GPI/LPS showed diminished autoantibody production compared to WT mice, but to a lesser extent than TRIF-deficient mice. We conclude that LPS-dependent TRIF signaling is required for the generation of autoantibody production in our induced SLE model, both through type I IFN-dependent and - independent effects. Supported by grants from CIHR (????)