Expression, Activation, and Function of Integrin alphaMbeta2 (Mac-1) on Neutrophil-Derived Microparticles

Blood. 2008 Sep 15;112(6):2327-35. doi: 10.1182/blood-2007-12-127183. Epub 2008 May 28.

Abstract

Leukocyte-derived microparticles (MPs) are markers of cardiovascular diseases and contribute to pathogenesis by their interaction with various cell types. The presence and activation state of a multifunctional leukocyte receptor, integrin alpha(M)beta(2) (CD11b/18), on MPs derived from human neutrophils (PMNs) were examined. alpha(M)beta(2) expression was significantly enhanced on MPs derived from stimulated compared with resting PMNs. Furthermore, alpha(M)beta(2) on MPs from stimulated but not resting PMNs was in an activated conformation because it was capable of binding activation-specific monoclonal antibodies (CBRM1/5 and mAb24) and soluble fibrinogen. MPs expressing active alpha(M)beta(2) interacted with and were potent activators of resting platelets as assessed by induction of P-selectin expression and activation of alpha(IIb)beta(3). With the use of function-blocking antibodies and MPs obtained from alpha(M)(-/-)-deficient mice, we found that engagement of GPIbalpha on platelets by alpha(M)beta(2) on MPs plays a pivotal role in MP binding. Platelet activation by MPs occurs by a pathway dependent on Akt phosphorylation. PSGL-1/P-selectin interaction also is involved in the conjugation of MPs to platelets, and the combination of blocking reagents to both alpha(M)beta(2)/GPIbalpha and to PSGL-1/P-selectin completely abrogates MP-induced platelet activation. Thus, cooperation of these 2 receptor/counterreceptor systems regulates the prothrombotic properties of PMN-derived MPs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers / analysis
  • Biomarkers / chemistry
  • Humans
  • Macrophage-1 Antigen / genetics
  • Macrophage-1 Antigen / metabolism*
  • Macrophage-1 Antigen / physiology
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Knockout
  • Neutrophils / chemistry*
  • Neutrophils / physiology
  • Platelet Activation*
  • Protein Binding
  • Protein Conformation

Substances

  • Biomarkers
  • Macrophage-1 Antigen
  • Membrane Glycoproteins
  • P-selectin ligand protein