Expression, activation, and function of integrin alphaMbeta2 (Mac-1) on neutrophil-derived microparticles.
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.
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic, OH 44195, USA.
Elzbieta
E
Pluskota
Neil M
NM
Woody
Dorota
D
Szpak
Christie M
CM
Ballantyne
Dmitry A
DA
Soloviev
Daniel I
DI
Simon
Edward F
EF
Plow
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000737:chemistry; D006801:Humans; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000737:chemistry* / Q000502:physiology; D015539:Platelet Activation; D011485:Protein Binding; D011487:Protein Conformation
D015415:Biomarkers; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein