Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins

Denise Lau, Hanke Mollnau, Jason P. Eiserich, Bruce A. Freeman, Andreas Daiber, Ursula M. Gehling, Jens Brümmer, Volker Rudolph, Thomas Münzel, Thomas Heitzer, Thomas Meinertz, Stephan Baldus

Research output: Contribution to journalArticle

264 Scopus citations

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 NFκB in 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 (O2 •-) production, which was prevented by anti-CD11b b 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.

Original languageEnglish (US)
Pages (from-to)431-436
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number2
DOIs
StatePublished - Jan 11 2005

Keywords

  • Atherosclerosis
  • Cytokine
  • Endothelium leukocyte
  • Nitric oxide

ASJC Scopus subject areas

  • Genetics
  • General

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    Lau, D., Mollnau, H., Eiserich, J. P., Freeman, B. A., Daiber, A., Gehling, U. M., Brümmer, J., Rudolph, V., Münzel, T., Heitzer, T., Meinertz, T., & Baldus, S. (2005). Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins. Proceedings of the National Academy of Sciences of the United States of America, 102(2), 431-436. https://doi.org/10.1073/pnas.0405193102