Serum extracellular traps associate with the activation of myeloid cells in SLE patients with the low level of anti-DNA antibodies

Neutrophil extracellular traps (NETs) are involved in systemic lupus erythematosus (SLE). We sought to cluster SLE patients based on serum NET levels. Serum NET levels were higher in SLE patients than healthy controls. Frequencies of pleuritis and myositis were increased in patients with high serum NET levels. Serum NET levels negatively correlated with anti–double stranded DNA (anti-dsDNA) antibody titers and C1q-binding immune complexes, but positively correlated with C-reactive protein (CRP) and monocyte counts. Neutrophil transcriptome analysis demonstrated no difference in NET-associated signatures, irrespective of serum NET levels, suggesting anti-dsDNA antibody-mediated clearance of NETs. In serum, NET levels were significantly correlated with myeloid cell-derived inflammatory molecules. Serum NET-based cluster analysis revealed 3 groups of patients based on serum NET and CRP levels, anti-dsDNA antibody titers, and monocyte count. Monocytes were consistently activated following NET-containing immune complex (NET-IC) stimulation. In conclusion, SLE patients with high serum NET levels had lower anti-dsDNA antibody titers and higher inflammatory responses. NET-IC-stimulated monocytes might associate with an inflammatory response characterized by elevated CRP levels. These findings can apply to precision medicine, as inflammatory processes, rather than antibody-dependent processes, can be targeted in specific subpopulations of SLE patients.