Type I interferon-dependent and -independent signaling underlie autoantibody production in a murine lupus model.

Systemic lupus erythematosus (SLE) is characterized by the development of autoantibodies against diverse self-antigens and damage to multiple organs. Immunization with the SLE autoantigen β2-glycoprotein I and lipopolysaccharide (LPS) induces a murine model of SLE with the sequential emergence of multiple hallmark SLE autoantibodies. LPS is a TLR4 trigger of innate immunity and inflammation that signals through adaptor proteins MyD88 and TRIF, resulting in the production of both inflammatory cytokines and type I interferons (IFN-I). We hypothesized that both IFN-I-dependent and -independent mechanisms are important in the initiation of SLE. Using our induced murine model of SLE, we found that TRIF deficiency completely abrogated autoantibody production. Downstream of TRIF, both IRF3 and IFNaR (IFN-I receptor) deficiency significantly diminished autoantibody production. Using transcriptomics, we identified 27 upregulated and 4 downregulated TRIF- and IRF3-dependent genes differentially expressed by both dendritic cells (DCs) and macrophages upon induction of the SLE model. While most genes were dependent on IFN-I signalling, some showed little or no IFN-I dependence. Notably, the 27 upregulated genes correlated with published datasets for human SLE. Our findings map the transcriptional response of macrophages and DCs early during pathogenesis of SLE, including pathways associated with both IFN-I-dependent and -independent genes in SLE. Investigation of candidate genes within both gene subsets may provide insight into the events leading up to SLE as well as potential therapeutic targets.