title: Extracellular superoxide dismutase is present in secretory vesicles of human neutrophils and released upon stimulation.
abstract: Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme present in the extracellular matrix (ECM), where it provides protection against oxidative degradation of matrix constituents including type I collagen and hyaluronan. The enzyme is known to associate with macrophages and polymorphonuclear leukocytes (neutrophils) and increasing evidence supports a role for EC-SOD in the development of an inflammatory response. Here we show that human EC-SOD is present at the cell surface of isolated neutrophils as well as stored within secretory vesicles. Interestingly, we find that EC-SOD mRNA is absent throughout neutrophil maturation indicating that the protein is synthesized by other cells and subsequently endocytosed by the neutrophil. When secretory vesicles were mobilized by neutrophil stimulation using formyl-methionyl-leucyl-phenylalanine (fMLF) or phorbol 12-myristate 13-acetate (PMA), the protein was released into the extracellular space and found to associate with DNA released from stimulated cells. The functional consequences were evaluated by the use of neutrophils isolated from wild-type and EC-SOD KO mice, and showed that EC-SOD release significantly reduce the level of superoxide in the extracellular space, but does not affect the capacity to generate neutrophil extracellular traps (NETs). Consequently, our data signifies that EC-SOD released from activated neutrophils affects the redox conditions of the extracellular space and may offer protection against highly reactive oxygen species such as hydroxyl radicals otherwise generated as a result of respiratory burst activity of activated neutrophils.
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Marie B
authors.initials: MB
authors.lastname: Iversen
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Randi H
authors.initials: RH
authors.lastname: Gottfredsen
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Ulrike G
authors.initials: UG
authors.lastname: Larsen
authors.affiliation: Department of Molecular Biology and Genetics, Interdisciplinary Nanoscience Center (iNANO), Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Enghild
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Jeppe
authors.initials: J
authors.lastname: Praetorius
authors.affiliation: Department of Hematology, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Borregaard
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark. Electronic address: svp@biomed.au.dk.
authors.forename: Steen V
authors.initials: SV
authors.lastname: Petersen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005110:Extracellular Space / Q000201:enzymology; D065206:Extracellular Traps / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051379:Mice; D018375:Neutrophil Activation; D009504:Neutrophils / Q000201:enzymology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst; D022142:Secretory Vesicles / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C441642:SOD3 protein, human; D013482:Superoxide Dismutase
keywords: Inflammation; Neutrophil; Reactive oxygen species (ROS); Redox regulation; Secretory vesicles; Superoxide dismutase (SOD)