Hemostasis Thrombosis and Vascular Biology: Expression activation and function of integrin αMβ2 (Mac-1) on neutrophil-derived microparticles

摘要

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 αMβ2 (CD11b/18), on MPs derived from human neutrophils (PMNs) were examined. αMβ2 expression was significantly enhanced on MPs derived from stimulated compared with resting PMNs. Furthermore, αMβ2 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 αMβ2 interacted with and were potent activators of resting platelets as assessed by induction of P-selectin expression and activation of αIIbβ3. With the use of function-blocking antibodies and MPs obtained from αM^−/−-deficient mice, we found that engagement of GPIbα on platelets by αMβ2 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 αMβ2/GPIbα 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.