title: Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients develop autoantibodies to DNA, histones, and often to neutrophil proteins. These form immune complexes that are pathogenic and may cause lupus nephritis. In SLE patients, infections can initiate flares and are a major cause of mortality. Neutrophils respond to infections and release extracellular traps (NETs), which are antimicrobial and are made of DNA, histones, and neutrophil proteins. The timely removal of NETs may be crucial for tissue homeostasis to avoid presentation of self-antigens. We tested the hypothesis that SLE patients cannot clear NETs, contributing to the pathogenesis of lupus nephritis. Here we show that serum endonuclease DNase1 is essential for disassembly of NETs. Interestingly, a subset of SLE patients' sera degraded NETs poorly. Two mechanisms caused this impaired NET degradation: (i) the presence of DNase1 inhibitors or (ii) anti-NET antibodies prevented DNase1 access to NETs. Impairment of DNase1 function and failure to dismantle NETs correlated with kidney involvement. Hence, identification of SLE patients who cannot dismantle NETs might be a useful indicator of renal involvement. Moreover, NETs might represent a therapeutic target in SLE.
authors.affiliation: Department of Cellular Microbiology and Microscopy Core Facility, Max-Planck Institute for Infection Biology, Berlin 10117, Germany.
authors.forename: Abdul
authors.initials: A
authors.lastname: Hakkim
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Fürnrohr
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Britta
authors.initials: B
authors.lastname: Laube
authors.forename: Ulrike Abu
authors.initials: UA
authors.lastname: Abed
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
authors.forename: Arturo
authors.initials: A
authors.lastname: Zychlinsky
mesh_terms: D003850:Deoxyribonuclease I / Q000378:metabolism*; D005110:Extracellular Space; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D008181:Lupus Nephritis / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000201:enzymology*
chemical_list: D003850:Deoxyribonuclease I