Expression, activation, and function of integrin alpha(M)beta(2) (Mac-1) on neutrophil-derived microparticles
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.
- SourceAvailable from: Peter Kruzliak
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- "All MPs are procoagulant since on their surface they contain anionic phospholipids, a substrate for formation of coagulation complexes. Interaction of leukocyte-derived MPs with platelets was demonstrated in model experiments by immune electron microscopy (Rauch et al. 2000) and flow cytometry (Del Conde et al. 2005; Pluskota et al. 2008). The exchange of specific proteins via production and uptake of MPs is an effective tool for coordination of complex cell reactions such as atherothrombosis or immune response. "
ABSTRACT: In acute myocardial infarction patients the injured vascular wall triggers thrombus formation in the damage site. Fibrin fibers and blood cellular elements are the major components of thrombus formed in acute occlusion of coronary arteries. It has been established that the initial thrombus is primarily composed of activated platelets rapidly stabilized by fibrin fibers. This review highlights the role of platelet membrane phenotype in pathophysiology of myocardial infarction. Here, we regard platelet phenotype as quantitative and qualitative parameters of the plasma membrane outer surface, which are crucial for platelet participation in blood coagulation, development of local inflammation and tissue repair.Biomarkers 12/2014; · 2.52 Impact Factor
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- "In addition to depositing paracrine signals, microvesicles have been shown to interact with cells in the tumor microenvironment, promoting signaling responses in the target cells (Fig. 2). Microvesicle–target cell interaction results in either the fusion of the microvesicle with the target cell or endocytosis of the microvesicle (Gasser et al. 2003; Losche et al. 2004; Eken et al. 2008; Pluskota et al. 2008). Here we discuss recent advances and speculations as to how individual sets of bioactive effectors—namely, proteins and nucleic acids—contained in TMVs can affect cancer progression. "
ABSTRACT: Recent advances in the study of tumor-derived microvesicles reveal new insights into the cellular basis of disease progression and the potential to translate this knowledge into innovative approaches for cancer diagnostics and personalized therapy. Tumor-derived microvesicles are heterogeneous membrane-bound sacs that are shed from the surfaces of tumor cells into the extracellular environment. They have been thought to deposit paracrine information and create paths of least resistance, as well as be taken up by cells in the tumor microenvironment to modulate the molecular makeup and behavior of recipient cells. The complexity of their bioactive cargo-which includes proteins, RNA, microRNA, and DNA-suggests multipronged mechanisms by which microvesicles can condition the extracellular milieu to facilitate disease progression. The formation of these shed vesicles likely involves both a redistribution of surface lipids and the vertical trafficking of cargo to sites of microvesicle biogenesis at the cell surface. Current research also suggests that molecular profiling of these structures could unleash their potential as circulating biomarkers as well as platforms for personalized medicine. Thus, new and improved strategies for microvesicle identification, isolation, and capture will have marked implications in point-of-care diagnostics for cancer patients.Genes & development 06/2012; 26(12):1287-99. DOI:10.1101/gad.192351.112 · 12.64 Impact Factor
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ABSTRACT: The small vesicles shed from the surface of many cells upon stimulation, considered for a long time to be artefacts, are now recognized as specific structures that are distinct from the exosomes released upon exocytosis of multivesicular bodies. Recent reports indicate that shedding vesicles participate in important biological processes, such as the surface-membrane traffic and the horizontal transfer of protein and RNAs among neighboring cells, which are necessary for the rapid phenotype adjustments in a variety of conditions. In addition, shedding vesicles have important physiological and pathological roles: in coagulation, by mediating the coordinate contribution of platelets, macrophages and neutrophils; in inflammatory diseases, via the release of cytokines; and in tumor progression, facilitating the spreading and release of cancer cells to generate metastases.Trends in cell biology 02/2009; 19(2):43-51. DOI:10.1016/j.tcb.2008.11.003 · 12.31 Impact Factor