Expression, activation, and function of integrin αMβ2 (Mac-1) on neutrophil-derived microparticles

Abstract

IntroductionLeukocyte-platelet cross-talk plays multiple and important roles in inflammatory and thrombotic responses. 1 Activated platelets and platelet-released mediators, such as PDGF and PAF, activate leukocytes enhancing their responses such as adhesion, chemotaxis, phagocytosis, and superoxide generation. [2][3][4][5] Conversely, activated leukocytes induce platelet activation as evidenced by increased platelet P-selectin expression. 6 In vivo studies show that leukocytes and platelets colocalize within atherosclerotic and restenotic lesions, at sites of hemorrhage and ischemia-reperfusion injury. [7][8][9][10] Indeed, increased levels of leukocyte-platelet aggregates are found in patients with diabetes, acute coronary syndromes, trauma, and sepsis. [11][12][13] Numerous studies have analyzed the receptors involved in leukocyte-platelet interactions. P-selectin on activated platelets binds PSGL-1 on leukocytes 14,15 to support their rolling on adherent platelets and to activate leukocyte integrin ␣ M ␤ 2 , which mediates firm leukocyte adhesion. [16][17][18] Several ␣ M ␤ 2 counterreceptors on platelets have been proposed, including Fg-bound ␣ IIb ␤ 3 , 19 GPIb␣,20,21 and JAM-3. 22 Recognition of these counterreceptors requires that ␣ M ␤ 2 be in an activated conformation. ␣ M ␤ 2 can be activated by stimulation of leukocytes by agonists and can be monitored with monoclonal antibodies (mAbs), CBRM1/5 and mAb24, which react selectively with the activated conformation.Microparticles (MPs) are released by membrane blebbing from cells undergoing activation or apoptosis. MPs are usually defined by 2 criteria: size (Ͻ 1 m) and surface expression of negatively charged phosphatidylserine (reviewed in Boulanger et al, 23 Morel et al, 24 Martinez et al, 25 and Distler et al 26 ). MPs are not simply the markers of cell activation or damage but may exert pleiotropic effects on blood and vascular cells. MPs of platelet and endothelial origin have procoagulant and proinflammatory activities (reviewed in Boulanger et al, 23 Morel et al, 24 Martinez et al, 25 and Distler et al 26 ) and are markers of acute coronary syndromes. 27,28 The functions of leukocyte-derived MPs are less clear. MPs shed by PMNs behave as inflammatory mediators and activate endothelial cells 29,30 but also exert antiinflammatory effects on macrophages. 31 One of the most important features of leukocyte-derived MPs is the expression of tissue factor 32 and negatively charged phospholipids, suggesting that they may contribute to blood coagulation. Indeed, in vivo studies have shown that leukocyte MPs are captured by activated platelets within thrombi by a P-selectin/PSGL-1-dependent mechanism that leads to accumulation of tissue factor and ultimately enhanced fibrin deposition. 33,34 Although the interactions of leukocyte-derived MPs with activated platelets have been well documented, additional mechanisms in which leukocyte MPs may activate resting platelets, when platelet P-selectin expression is low, have not been examined. In this study, we show...

Thrombocytopenia and hemostatic disorders in chronic graft versus host disease

“…95 According to a recently published study, leukocyte-derived microparticles also act as a novel platelet agonist targeting GPIba, a platelet-adhesion receptor important for initiation of clot formation by binding von Willebrand factor (vWF); such leukocyte-platelet interactions are amplified in situation when neutrophils are also activated. 95,96 It is important to note the link between vWF, endothelial injury, and cGVHD described by Biedermann et al 97 They found that cGVHD patients have extensive loss of microvessels in affected tissues and increased circulating vWF concentrations, concluding that vWF was released from vascular endothelial cells injured in process of cGVHD. 97 In summary, involvement of microparticles formation in coagulation, inflammation, and vascular problems, as well as in other platelet-leukocyte-endothelial processes and interactions, 98 could have important roles in the pathophysiology of tissue damage found in cGVHD.…”

Changing world of neutrophils

“…In another study, stimulation of neutrophils with bacterial endotoxin resulted in shedding of PAF containing microparticles which activated platelets [118]. More recently, the active form of the β2 integrin Mac-1was detected on the surface of EVs released from activated neutrophils, and the active integrin played a central role in binding to and activation of resting platelets [84].…”

Microvesicles: mediators of extracellular communication during cancer progression

“…Microvesicles shed from neurons and astrocytes contain growth factors and promote paracrine responses (Proia et al, 2008;Schiera et al, 2007). In addition, membrane proteins on microvesicles have been shown to interact specifically with molecules on target cells to promote signaling responses (Eken et al, 2008;Gasser et al, 2003;Losche et al, 2004;Pluskota et al, 2008). In some cases, direct binding results in fusion of the microvesicle with the target cell or endocytosis of the microvesicle.…”