Expression, activation, and function of integrin αMβ2 (Mac-1) on neutrophil-derived microparticles
Expression, activation, and function of integrin αMβ2 (Mac-1) on neutrophil-derived microparticles
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DOI：
10.1182/blood-2007-12-127183
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发表时间：
2008-09-15
期刊：
影响因子：
20.3
通讯作者：
Plow, Edward F.
中科院分区：
文献类型：
--
作者：
Pluskota, Elzbieta;Woody, Neil M.;Plow, Edward F.
白细胞衍生的微粒（MP）是心血管疾病的标志物，并通过与各种细胞类型的相互作用而导致发病。检测了多功能白细胞受体整合素α（M）β（2）（CD 11b/18）在人中性粒细胞（PMN）MP上的存在和活化状态。与静息的PMNs相比，在刺激的PMNs衍生的MP上α（M）β（2）的表达显著增强。此外，来自刺激的而非静息的PMN的MP上的α（M）β（2）处于活化构象，因为它能够结合活化特异性单克隆抗体（CBRM 1/5和mAb 24）和可溶性纤维蛋白原。表达活性α（M）β（2）的MP与静息血小板相互作用，并且是静息血小板的有效激活剂，如通过诱导P-选择素表达和α（IIb）β（3）的激活所评估的。通过使用从α（-/-）（M）缺陷小鼠获得的功能阻断抗体和MP，我们发现MP上的α（M）β（2）与血小板上的GPIb α的接合在MP结合中起关键作用。MP通过依赖于Akt磷酸化的途径激活血小板。PSGL-1/P-选择素相互作用也参与MP与血小板的缀合，并且与α（M）β（2）/GPIb α和PSGL-1/P-选择素两者的阻断剂的组合完全消除MP诱导的血小板活化。因此，这2个受体/反受体系统的合作调节PMN衍生的MP的促血栓性质。
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 GPIb alpha 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)/GPIb alpha 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.