Identification of Lupus Immune Complex-Driven Pathogenic Pro-inflammatory Monocytes and Macrophages in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE or lupus), an autoimmune disease characterized by autoantibody production and inflammation, exhibits clinicopathologic heterogeneity. Here we investigated the heterogeneity and functions of mononuclear phagocytes (MPs), including monocytes (Mo) and macrophages (MΦ), driven by lupus immune complex (IC) stimulation. Our single cell RNA sequencing (scRNA-seq) analysis of human Mo incubated with U1-snRNP lupus IC revealed an expansion of pro-inflammatory Mo with increased expression of inflammatory genes including cytokines, chemokines, and transcription factors. These transcriptomic changes were reflected at the protein level, with a strong correlation between gene and protein expression, as determined by proteomic analysis. Mo developed similar pro-inflammatory transcriptomic changes in response to other IC containing dsDNA and Ro60. Interrogation of scRNA-seq datasets from the skin, kidneys, and peripheral blood of lupus patients revealed the presence and expansion of pro-inflammatory Mo and MΦ populations, with transcriptomic signatures similar to those seen in lupus IC-stimulated Mo. Some of these cells with increased expression of the snRNP IC gene signature exhibited low expression of the type I IFN signature, suggesting that lupus IC and type I IFN stimulation may independently affect Mo subsets. In lupus nephritis tissue, infiltration of CD68+ cells expressing NLRP3, a molecule upregulated in Mo stimulated with snRNP IC, was associated with treatment outcomes, supporting an important role for MPs in lupus nephritis. Collectively, our findings provide novel insights into the critical role of pro-inflammatory MPs arising from lupus IC stimulation in the pathogenesis of SLE.