title: Ligation of signal inhibitory receptor on leukocytes-1 suppresses the release of neutrophil extracellular traps in systemic lupus erythematosus.
abstract: 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.
authors.affiliation: Department of Immunology, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Avondt
authors.forename: Ruth
authors.initials: R
authors.lastname: Fritsch-Stork
authors.forename: Ronald H W M
authors.initials: RH
authors.lastname: Derksen
authors.forename: Linde
authors.initials: L
authors.lastname: Meyaard
mesh_terms: D000328:Adult; D000906:Antibodies / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D065206:Extracellular Traps / Q000276:immunology*; D005260:Female; D006801:Humans; D008026:Ligation / Q000379:methods; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D010586:Phagocytes / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology*
chemical_list: D000906:Antibodies; D011971:Receptors, Immunologic; C550469:VSTM1 protein, human; D019255:NADPH Oxidases