Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins.
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.
Lau
Denise
D
Departments of Cardiology, Hepatobiliary Surgery, and Clinical Chemistry, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
Mollnau
Hanke
H
Eiserich
Jason P
JP
Freeman
Bruce A
BA
Daiber
Andreas
A
Gehling
Ursula M
UM
Brümmer
Jens
J
Rudolph
Volker
V
Münzel
Thomas
T
Heitzer
Thomas
T
Meinertz
Thomas
T
Baldus
Stephan
S
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
D039481:CD11b Antigen; D018821:CD18 Antigens; D016328:NF-kappa B; D013481:Superoxides; D009195:Peroxidase; D048051:p38 Mitogen-Activated Protein Kinases