Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis 
of systemic Lupus erythematosus (SLE), since netting neutrophils release 
potentially immunogenic autoantigens including histones, LL37, human neutrophil 
peptide (HNP), and self-DNA. In turn, these NETs activate plasmacytoid dendritic 
cells resulting in aggravation of inflammation and disease. How suppression of 
NET formation can be targeted for treatment has not been reported yet. Signal 
Inhibitory Receptor on Leukocytes-1 (SIRL-1) is a surface molecule exclusively 
expressed on phagocytes. We recently identified SIRL-1 as a negative regulator 
of human neutrophil function. Here, we determine whether ligation of SIRL-1 
prevents the pathogenic release of NETs in SLE. Peripheral blood neutrophils 
from SLE patients with mild to moderate disease activity and healthy donors were 
freshly isolated. NET release was assessed spontaneously or after exposure to 
anti-neutrophil antibodies or plasma obtained from SLE patients. The formation 
of NETs was determined by microscopic evaluation using DNA dyes and 
immunostaining of NET components, as well as by live cell imaging. We show that 
SLE neutrophils spontaneously release NETs. NET formation is enhanced by 
stimulation with antibodies against LL37. Inhibition of nicotinamide adenine 
dinucleotide phosphate (NADPH) oxidase activity and MEK-ERK signaling prevents 
NET release in response to these antibodies. Signaling via the inhibitory 
receptor SIRL-1 was induced by ligation with anti-SIRL-1 specific antibodies. 
Both spontaneous and anti-neutrophil antibody-induced NET formation is 
suppressed by engagement of SIRL-1. Furthermore, NET release by healthy 
neutrophils exposed to SLE plasma is inhibited by SIRL-1 ligation. Thus, SIRL-1 
engagement can dampen spontaneous and anti-neutrophil antibody-induced NET 
formation in SLE, likely by suppressing NAPDH oxidase and MEK-ERK activity. 
Together, these findings reveal a regulatory role for SIRL-1 in NET formation, 
potentially providing a novel therapeutic target to break the pathogenic loop in 
SLE.