Ongoing inflammation including activation of the complement system is a hallmark 
of systemic lupus erythematosus (SLE). Antimicrobial neutrophil extracellular 
traps (NETs) are composed of secreted chromatin that may act as a source of 
autoantigens typical for SLE. In this study, we investigated how complement 
interacts with NETs and how NET degradation is affected by complement in SLE 
patients. We found that sera from a subset of patients with active SLE had a 
reduced ability to degrade in vitro-generated NETs, which was mostly restored 
when these patients were in remission. Patients that failed to degrade NETs had 
a more active disease and they also displayed lower levels of complement 
proteins C4 and C3 in blood. We discovered that NETs activated complement in 
vitro and that deposited C1q inhibited NET degradation including a direct 
inhibition of DNase-I by C1q. Complement deposition on NETs may facilitate 
autoantibody production, and indeed, Abs against NETs and NET epitopes were more 
pronounced in patients with impaired ability to degrade NETs. NET-bound 
autoantibodies inhibited degradation but also further increased C1q deposition, 
potentially exacerbating the disease. Thus, NETs are a potent complement 
activator, and this interaction may play an important role in SLE. Targeting 
complement with inhibitors or by removing complement activators such as NETs 
could be beneficial for patients with SLE.