title: Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins.
abstract: Recruitment and activation of polymorphonuclear neutrophils (PMNs) reflects a primary immunological response to invading pathogens and has also emerged as a hallmark of vascular inflammation. One of the principal enzymes released upon PMN activation is myeloperoxidase (MPO), a heme protein that not only generates cytotoxic oxidants but also impacts deleteriously on nitric oxide-dependent signaling cascades within the vasculature. Because MPO also associates with the membrane of PMN, we evaluated whether MPO could also function as an autocrine modulator of PMN activation. The extent of PMN membrane-associated MPO was elevated in patients with acute inflammatory vascular disease compared with healthy individuals. Isolated PMNs bound free MPO by a CD11b/CD18 integrin-dependent mechanism. PMNs exposed to MPO were characterized by increased tyrosine phosphorylation and p38 mitogen-activated protein kinase activation. Also, nuclear translocation of NFkappaBin PMN was enhanced after incubation with MPO, as was surface expression of CD11b. Binding of PMN to MPO-coated fibronectin surfaces amplified PMN degranulation, as evidenced by increased release of MPO and elastase. MPO also augmented PMN-dependent superoxide (O(2)(*-)) production, which was prevented by anti-CD11b antibodies, but not MPO inhibitors. Collectively, these results reveal that binding of MPO to CD11b/CD18 integrins stimulates PMN signaling pathways to induce PMN activation in a mechanism independent of MPO catalytic activity. These cytokine-like properties of MPO thus represent an additional dimension of the proinflammatory actions of MPO in vascular disease.
authors.affiliation: Departments of Cardiology, Hepatobiliary Surgery, and Clinical Chemistry, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Lau
authors.forename: Hanke
authors.initials: H
authors.lastname: Mollnau
authors.forename: Jason P
authors.initials: JP
authors.lastname: Eiserich
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Ursula M
authors.initials: UM
authors.lastname: Gehling
authors.forename: Jens
authors.initials: J
authors.lastname: Brümmer
authors.forename: Volker
authors.initials: V
authors.lastname: Rudolph
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Heitzer
authors.forename: Thomas
authors.initials: T
authors.lastname: Meinertz
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
mesh_terms: D039481:CD11b Antigen / Q000502:physiology*; D018821:CD18 Antigens / Q000502:physiology*; D015550:Cell Degranulation; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D018375:Neutrophil Activation; D009195:Peroxidase / Q000502:physiology*; D010766:Phosphorylation; D013481:Superoxides / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D018821:CD18 Antigens; D016328:NF-kappa B; D013481:Superoxides; D009195:Peroxidase; D048051:p38 Mitogen-Activated Protein Kinases