Cell-derived microparticles : composition and function
Biró, É.
Publication date
2008
Document Version
Final published version
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Citation for published version (APA):
Biró, É. (2008). Cell-derived microparticles : composition and function.
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ell-derived microparticles
omposition and function
Éva Biró
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Cell-derived microparticles – Composition and function Éva Biró
PhD thesis, University of Amsterdam, Amsterdam, the Netherlands ISBN: 978-90-9023572-1
Layout and cover design: Éva Biró Printed by: Ponsen & Looijen B.V.
© 2008 by É. Biró, Leiderdorp, the Netherlands
Publication of this thesis was generously sponsored by the E.C. Noyons Stichting and Instrumentation Laboratory.
ell-derived microparticles
omposition and function
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CADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam
op gezag van de Rector Magnificus prof. dr. D.C. van den Boom
ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel
op dinsdag 18 november 2008, te 12:00 uur door
Éva Biró
geboren te Debrecen, Hongarije
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Promotiecommissie
Promotor: Prof. dr. A. Sturk Co-promotor: Dr. R. Nieuwland Overige leden: Prof. dr. J.M.F.G. Aerts
Prof. dr. H.R. Büller Prof. dr. L. Eijsman Prof. dr. J.I. Kappelmayer Prof. dr. B.A.J.M. de Mol Prof. dr. C.J.F. van Noorden
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General introduction
Chapter 1 General introduction, aims and outline of this thesis 13
Section I
Microparticle analysis
Chapter 2 Measuring circulating cell-derived microparticles: A flow 41 cytometric method of microparticle analysis
J Thromb Haemost 2004; 2: 1843-1844.
Section II Composition and procoagulant properties of
microparticles
Chapter 3 The phospholipid composition and cholesterol content 47
of platelet-derived microparticles: A comparison with platelet membrane fractions
J Thromb Haemost 2005; 3: 2754-2763.
Chapter 4 Human cell-derived microparticles promote thrombus 69
formation in vivo in a tissue factor-dependent manner
J Thromb Haemost 2003; 1: 2561-2568.
Chapter 5 Phospholipid composition of in vitro endothelial 87
microparticles and their in vivo thrombogenic properties
Thromb Res 2008; 121: 865-871.
Chapter 6 P-selectin- and CD63-exposing platelet microparticles 101 reflect platelet activation in peripheral arterial disease
and myocardial infarction
Clin Chem 2006; 52: 657-664.
Chapter 7 Plasma markers of coagulation and endothelial activation 117
in Fabry disease: Impact of renal impairment
Section III Complement activation on the surface of
microparticles
Chapter 8 Targeting complement in rheumatoid arthritis 137
Current Rheumatology Reviews 2008; in press.
Chapter 9 Activated complement components and complement 165
activator molecules on the surface of cell-derived microparticles in patients with rheumatoid arthritis and healthy individuals
Ann Rheum Dis 2007; 66: 1085-1092.
Chapter 10 Complement activation on the surface of cell-derived 183 microparticles during cardiac surgery with
cardiopulmonary bypass: Is retransfusion of pericardial blood harmful?
Submitted.
Chapter 11 Complement activation on cell-derived microparticles 199 in myocardial infarction is mediated by immunoglobulin G and not C-reactive protein
Submitted.
Chapter 12 Cell-derived microparticles and complement activation 213 in preeclampsia versus normal pregnancy
Placenta 2007; 28: 928-935.
Summary / Samenvatting
Chapter 13 Summary 231 Chapter 14 Samenvatting 237Acknowledgements
245Curriculum vitae
251List of publications
255C
HAPTER
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General introduction, aims and outline of
ell-derived microparticles were observed experimentally as early as 1946, when Chargaff and West published their findings that the clotting time of plasma, obtained by centrifugation at 1900 × g, is prolonged by centrifugation at 31000 ×
g, and that “the clotting factor of which the plasma is deprived by high-speed centrifugation
is found in a minute pellet whose sedimentation is brought about by this operation” [1]. In 1967, Wolf published a study “to provide evidence for the occurrence in normal plasma, serum and fractions derived therefrom of coagulant material in minute particulate form, sedimentable by high-speed centrifugation and originating from platelets, but distinguishable from intact platelets”. He called this coagulant material “platelet dust” [2].
During the last 20-30 years extensive research has been done on cell-derived microparticles. We now know that they can be released not only from platelets, but also from erythrocytes, leukocytes, endothelial cells, and diverse other cell types, and that such microparticles are not only present in the circulation but also in other body fluids, such as synovial and cerebrospinal fluids [3-5].
Microparticles are released by a budding process from the surface membrane of the cells upon activation or apoptosis, and according to the definition formulated at a 2005 Scientific Subcommittee Meeting of the Working Group of Vascular Biology of the International Society on Thrombosis and Haemostasis, they are 0.1–1 μm vesicular structures of diverse cellular origin that lack a nucleus or synthetic capability, but may contain a membrane skeleton, and varying amounts of surface-exposed phosphatidylserine (PS). Their composition and function depend upon their cellular origin and the inducer of the vesiculation.
In vivo, the numbers, cellular origin, composition and function of the microparticles
vary depending on the body fluid analyzed, as well as the pathophysiological state of the individual. This relationship between microparticles and pathophysiological processes is complex and two-way, since the formation and composition of microparticles can be influenced by diverse pathophysiological phenomena as well as medication and, in turn, microparticles can aggravate or attenuate certain pathophysiological processes.
Processes leading to microparticle release from cells
Microparticles are released from their parent cells upon activation or apoptosis by a budding process, resulting in right-side out vesicles, as also documented by electron microscopy [6-10].
Cell activation
Activation of platelets for example with collagen, thrombin, collagen plus thrombin, by adhesion to von Willebrand factor under high shear stress, or by incubation with sera from patients with heparin-induced thrombocytopenia in the presence of heparin [11-14] results
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in the formation of platelet-derived microparticles. Similarly, stimulation of leukocytes or endothelial cells with lipopolysaccharide (LPS) or cytokines such as tumor necrosis factor-α (TNFfactor-α) or interleukin (IL)-1 [9,15-17] causes the release of microparticles from these cells. These stimuli act via a membrane receptor. The ligand-receptor interaction induces changes in the intracellular concentrations of second messengers such as calcium ions and, in turn, these second messengers influence the activity of protein kinases and phosphatases and activate calpain, a calcium-dependent cysteine protease. Subsequently, the cytoskeleton is reorganized / degraded, resulting in membrane blebbing and release of microparticles [8,12,18-21]. Alternatively, stimulation by the membrane attack complex C5b-9 of the complement system, which forms lytic pores in cell membranes, or addition of a calcium ionophore (e.g. A23187) can directly increase the intracellular calcium concentration, resulting in similar downstream effects as described above, in platelets [18,20-22], as well as in erythrocytes [23-25], leukocytes [26,27], and endothelial cells [28].
The involvement of the integrin αIIbβ3 in platelet microparticle formation has also been
investigated. Integrin αIIbβ3 or glycoprotein (GP)IIb-IIIa is the most abundant receptor on
the platelet surface [29] and is involved in inside-out and outside-in signaling processes as well as platelet aggregation [30]. It has been reported that this complex is required for microparticle formation upon stimulation of platelets with various agonists [31], but other studies have found that it has no or only a limited role [32-34]. Evidence has also been presented that upon storage of platelets, in the absence of agonists and with only minor platelet activation, release of platelet-derived microparticles is dependent upon αIIbβ3
signaling, with a lesser role for calpain activity [35]. Other studies, however, gave contradictory results, showing a role for platelet activation processes in microparticle formation during storage [36], or a role for apoptosis-like events mediated either by caspases or calpain (see below) [37-40]. A role for αIIbβ3 in regulating the activation of
calpain has also been described [41]. In summary, the precise role of this integrin in microparticle generation during activation with different agonists still needs to be clarified.
Apoptosis
Apoptosis, a form of programmed cell death, is characterized by cell shrinkage, loss of membrane asymmetry and exposure of PS, nuclear condensation, DNA fragmentation, the release of apoptotic membrane blebs, and the formation of apoptotic bodies [42-45]. A family of cysteine proteases called caspases plays a central role in the apoptotic machinery [46]. Membrane blebbing can be induced by the Rho-associated kinase ROCK I, which is cleaved and thereby activated by caspases. Activated ROCK I subsequently contributes to phosphorylation of myosin light chains, myosin ATPase activity, and coupling of actin-myosin filaments to the plasma membrane, thus promoting membrane blebbing and relocalization of fragmented DNA into blebs and apoptotic bodies [47,48]. Another possible mechanism is cleavage and thereby activation of the Rho-associated kinase ROCK II by granzyme B during granule exocytosis-mediated cell death, employed for example by
NK cells and cytotoxic T lymphocytes. Activated ROCK II causes membrane blebbing in a manner similar to ROCK I [49].
Treatment of endothelial cells with mitomycin C, camptothecin or staurosporin, or growth factor deprivation of these cells all result in apoptosis and release of microparticles [50-53].
Although apoptosis is a process pertaining to nucleated cells, some platelet activation processes such as PS exposure and microparticle formation resemble apoptotic events, and platelets also contain several caspases [37,54,55]. Whether these caspases play a role in PS exposure and microparticle formation in platelets upon stimulation with agonists such as thrombin, collagen plus thrombin or calcium ionophore A23187, is currently a matter of discussion, and a role for calpain instead of caspases has also been proposed [54-57]. Similarly, apoptosis-like events in platelets during storage have been linked to activation of caspases in some studies, but others have disputed this and again suggested a role for calpain in these processes [37-40].
Erythrocytes can also undergo morphological alterations resembling apoptosis, including PS exposure and microparticle release, and these cells have also been shown to contain caspases and other components of the apoptotic machinery. However, as is the case with platelets, the role of caspases in the apoptosis-like events occurring in erythrocytes is controversial [58,59]. Regarding microparticle release from erythrocytes upon storage, it has been postulated that under these conditions the normal aging process of these cells is accelerated, and that this aging process resembles apoptosis, also regarding the mechanism of microparticle release [60,61].
Composition of cell-derived microparticles
LipidsMicroparticles are surrounded by a lipid bilayer composed mainly of phospholipids and cholesterol. This lipid bilayer is formed by budding and subsequent release of a part of the outer membrane of the parent cell (Figure 1). The exact lipid composition of the released microparticle is dependent upon the type of cell from which it was released and certain (patho)physiological processes that can modify the lipid composition of membranes.
Cell-derived microparticles isolated from venous blood of healthy individuals, originating predominantly from platelets but also from erythrocytes, leukocytes and endothelial cells [4], contain mostly phosphatidylcholine (PC) and sphingomyelin (SM), with smaller amounts of phosphatidylethanolamine (PE), PS, and phosphatidylinositol (PI), and minute quantities of the lysophospholipids lyso-PC, lyso-PE and lyso-PS [62]. Platelet-derived microparticles made in vitro by stimulating washed platelets with collagen differ from this in that they contain less PC and more SM, PE and PS [63]. Quite different is the phospholipid composition of microparticles isolated from synovial fluid of inflamed joints.
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Resting cell
Activated cell
Microparticles
Figure 1. Schematic representation of the formation and composition of microparticles. Intact resting cells have an asymmetric phospholipid distribution between the inner and outer leaflet of their plasma membrane, with the aminophospholipids PS and PE (depicted in black) located predominantly in the inner (cytoplasmic) leaflet, and the outer leaflet composed mainly of the choline-containing phospholipids PC and SM (depicted in white). Upon activation of the cell (and upon apoptosis), this phospholipid asymmetry collapses and the aminophospholipids PS and PE become exposed on the outer leaflet as well. Furthermore, depending on the cell type, granule secretion might occur upon activation, via fusion of the granule membranes with the plasma membrane of the cell.
Microparticles are formed by budding and subsequent release of the plasma membrane of activated (or apoptotic) cells. Proteins (depicted in gray) found in or associated with the plasma membrane and proteins found in the cytoplasma can also partition into the microparticles that are being released, either selectively or in a random manner.
PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; SM, sphingomyelin
These microparticles are derived mainly from leukocytes and only to a small extent from erythrocytes and platelets [64], and contain less PC, more PE, and very high quantities of lysophospholipids compared with microparticles of healthy individuals [3]. The high quantities of lysophospholipids can be explained by the high concentrations of secretory phospholipase A2 (sPLA2) in the synovial compartment, which can hydrolyze the sn-2 ester
Important to mention is that intact resting cells have an asymmetric phospholipid distribution between the inner and outer leaflet of their plasma membrane, whereby the aminophospholipids PS (which is negatively charged) and PE (which is neutral) are located mainly in the inner leaflet, and the outer leaflet is composed mostly of the choline-containing (neutral) phospholipids PC and SM. This asymmetric phospholipid distribution is actively maintained by enzymes such as the ATP-dependent aminophospholipid translocase and floppase. Inhibition of these enzymes, particularly the aminophospholipid translocase, and activation of a lipid scramblase results in the collapse of this phospholipid asymmetry and the exposure of negatively charged phospholipids in the outer leaflet of the plasma membrane [65]. This is known to occur upon cell activation as well as apoptosis [15,44,45,66-68], processes that also result in microparticle release from the plasma membrane of the cells, as described above. Several studies have found that the phospholipid distribution of the lipid bilayer surrounding the microparticles is also symmetric, with the microparticles exposing PS on their surface [68-71]. This can be visualized for example by using fluorescently labeled annexin V (formerly also called, among several other names, placental anticoagulant protein I), a protein that binds to PS-containing membranes in the presence of calcium ions [72,73]. However, a few investigators have also reported the presence of microparticles without negatively charged phospholipids on their surface, i.e. with an asymmetric phospholipid distribution [52,74,75], questioning the assumption that PS exposure is a general characteristic of microparticles.
Lipid rafts are cholesterol- and sphingolipid-rich membrane microdomains that play an important role in membrane trafficking, protein sorting and signal transduction [76-78]. The fact that certain proteins associated with lipid rafts are selectively enriched in microparticles (see below) suggests that the lipid rafts themselves, and thus the lipids found in them, might also be enriched in microparticles compared to their parent cells. The enrichment of raft lipids, however, has not been directly investigated.
Proteins
Proteins in cells are either found in or associated with the plasma membrane, or are found within the cell, in the cytoplasma, associated with cell organelles, or in the nucleus. Upon formation of microparticles, these proteins can partition into the microparticles that are being released (Figure 1). Some of them are specific for the parent cell type, and thus enable the determination of the cellular origin of the microparticles.
There is evidence that some proteins are selectively sorted into microparticles, i.e. they are enriched or depleted in the microparticles compared to their parent cells. For example in erythrocyte-derived microparticles, depletion of spectrin and enrichment of acetylcholinesterase, decay accelerating factor (DAF), CD59, stomatin, and complement receptor 1 has been described [79-84]. Stomatin and the glycosylphosphatidylinositol-anchored acetylcholinesterase, DAF and CD59 are proteins associated with lipid rafts [78,85], and their enrichment in the microparticles compared with their parent cells
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suggests that the lipid rafts themselves might be preferentially sorted into microparticles, or that the rafts are in some other way implicated in the process of microparticle formation. Enrichment of stomatin has also been shown in platelet-derived microparticles [86]. In monocyte-derived microparticles, the enrichment of tissue factor (TF) and P-selectin glycoprotein ligand-1 (PSGL-1), and the depletion of CD45 has been demonstrated, and the first two proteins have also been shown to localize to lipid rafts [87].
The proteins found in microparticles derived from a certain cell type can also vary depending upon the stimulus that induces the release of these microparticles. This has been extensively described for several surface antigens found on endothelial cells, stimulated to release microparticles by activation or apoptosis [17,52].
Regarding intracellular proteins, very little data are available. The finding that platelet-derived microparticles contain platelet factor XIII (subunit composition a2) but not plasma
factor XIII (subunit composition a2b2) provides extra evidence that such microparticles are
formed by a budding process [88]. Furthermore, recent studies have shown that caspase 3 is present in microparticles released from endothelial cells, and that inhibition of microparticle release results in caspase 3 accumulation in the cells, causing their increased apoptosis and detachment [53,89]. In platelet-derived microparticles released during storage of platelets, only procaspase 3 is present during the first few days of storage. Caspase 3 in the microparticles can only be detected from the 7th day onward, probably as a result of
procaspase 3 processing by caspase 9, which is also present in the microparticles [90]. The exact significance of these findings still has to be determined.
In recent years large-scale protein identification studies have become feasible using a proteomic approach. This has also been applied, though to a very limited extent, to the analysis of microparticles. Microparticles isolated from plasma, platelet-derived microparticles generated in vitro using adenosine diphosphate (ADP), endothelial cell-derived microparticles generated using TNFα with concomitant serum-deprivation, and erythrocyte-derived microparticles generated during blood bank storage have been analyzed, and hundreds of proteins identified, including those found intracellularly. Furthermore, the proteome of erythrocyte-derived microparticles has been semiquantitatively compared to that of erythrocyte membranes, again illustrating the selective sorting of proteins into the released microparticles [91-95].
Functions of cell-derived microparticles
Thrombosis and hemostasisCoagulation activation in vivo occurs predominantly via TF and factor VII [96]. Several ensuing steps in the coagulation activation cascade are dependent upon a negatively charged phospholipid surface upon which complexes of coagulation factors can assemble. These complexes bind to the phospholipid surface in the presence of calcium ions via the
negatively charged N-terminal domains of the vitamin K-dependent factors II, VII, IX and X. These N-terminal domains, also called Gla domains, contain several γ-carboxyglutamic acid (Gla) residues, which are created by the posttranslational vitamin K-dependent carboxylation of glutamic acid residues in the liver [97].
Microparticles can expose PS, thereby providing a negatively charged phospholipid surface [68-71], and may also expose TF, as demonstrated on in vitro [15-17,98-100] as well as in vivo released microparticles [64,101-104]. This provides the basis for their procoagulant properties. In addition, they may also have indirect effects on coagulation by inducing the expression of TF in various cell types. For instance, microparticles released from leukocytes stimulated by a chemotactic peptide as well as microparticles released from apoptotic monocytes induce TF expression by endothelial cells in culture [105,106]. Conversely, endothelial cell-derived microparticles generated in vitro bind to monocytic cells and induce the expression of TF on them. This is partly dependent on the interaction between intercellular adhesion molecule (ICAM)-1 on the microparticles and β2 integrins
on the monocytic cells [107].
Evidence that microparticles are indeed procoagulant is available on several levels. First, increased concentrations of circulating cell-derived microparticles are present in clinical conditions associated with a thromboembolic tendency, such as heparin-induced thrombocytopenia [13], patients with lupus anticoagulant [9], the antiphospholipid syndrome [108], systemic lupus erythematosus [109], cerebrovascular accidents [110], acute coronary syndromes [111,112], venous thromboembolism [113], or patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) [114]. Second, the decreased capacity of platelets to generate microparticles upon stimulation in Scott syndrome and a disorder described by Castaman et al. [11,115] is associated with a bleeding tendency. Third, microparticles isolated from blood or other body fluids of healthy individuals or patients suffering from various diseases initiate and support coagulation in
vitro [4,64,101,109,116-118]. Microparticles isolated from venous blood of healthy
individuals (originating predominantly from platelets, but also from erythrocytes, leukocytes and endothelial cells) cause a low but significant coagulation activation in vitro that is independent of TF/factor VII [4], whereas microparticles from the pericardial blood of patients undergoing cardiac surgery (originating mainly from erythrocytes, but also from other cell types such as platelets and leukocytes) and those isolated from synovial fluid of arthritic patients (derived mainly from leukocytes, and only to a small extent from erythrocytes and platelets), for example, initiate coagulation in a TF/factor VII-dependent manner [64,116]. Fourth, microparticles made in vitro by stimulation of platelets with the calcium ionophore A23187 are thrombogenic in an arterio-venous shunt model in rats [119].
Studies on the possible mechanisms underlying the procoagulant effect of microparticles have shown the binding of activated coagulation factors V and X (denoted factors Va and Xa), which form the prothrombinase complex, and the binding of factors
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VIII and IXa, which, when both activated, comprise the tenase complex. The exact nature of the binding sites for these coagulation factors still remains to be determined, and the involvement of specific receptors in addition to the negatively charged phospholipid surface cannot as yet be excluded [28,120-123]. Further investigations have shown in vitro the association of procoagulant platelet-derived microparticles with fibrin during thrombus formation [124] as well as the transfer of TF from leukocytes to platelets via microparticles released from the leukocytes. This transfer of TF is dependent on the interaction of the LewisX antigen (CD15) on the leukocyte-derived microparticles with P-selectin on the
platelets [125]. (P-selectin or CD62P is an adhesion molecule present in the α-granule membranes of resting platelets and exposed on the platelet surface upon activation and secretion of the granule contents [126,127].) In addition, using an in vivo laser-induced endothelial injury model in mice and real-time imaging using intravital high-speed microscopy, the binding of in vitro generated monocyte-derived microparticles exposing TF was shown to activated platelets in developing thrombi, mediated by the binding of PSGL-1 on the microparticles to P-selectin on the platelets [128].
Finally, it must be mentioned that microparticles can also have anticoagulant properties by binding and promoting the activity of protein C. Protein C is a vitamin K-dependent anticoagulant protein, which in its active form and in the presence of its (also vitamin K-dependent) cofactor, protein S, cleaves and thereby inactivates factors Va and VIIIa. It is activated by thrombin bound to thrombomodulin [129]. In a study of factor Va inactivation by activated protein C on resting and activated platelets, it was found that platelet activation by thrombin, collagen, or the calcium ionophore A23187 (but not ADP or adrenalin) resulted in acceleration of factor Va inactivation when compared with non-activated platelets, and that about 25% of the anticoagulant activity of the platelet suspensions was associated with the microparticles released from the platelets [130]. Also, it was shown that protein S binds to platelet-derived microparticles via its Gla domain and stimulates the binding of protein C as well as activated protein C to these microparticles [131]. Furthermore, the presence of the endothelial protein C receptor (EPCR) has been demonstrated on microparticles released from cultured endothelial cells or monocytes isolated from human blood, stimulated with activated protein C or TNFα. EPCR is a transmembrane protein (located primarily on the endothelium of large blood vessels but also on monocytes and neutrophil and eosinophil granulocytes) that binds protein C and enhances its activation by the thrombin/thrombomodulin complex [132-135]. The microparticle-associated EPCR was full-length, and when using activated protein C as a stimulus, also contained bound activated protein C, which retained its anticoagulant activity [136]. Presumably, the relative contribution of the pro- and anticoagulant properties of microparticles to their overall hemostatic function depends on the specific conditions that are being investigated.
Inflammation
Cell-derived microparticles play a role in inflammatory processes in various ways. First, by transporting and transferring bioactive molecules or through direct receptor-ligand interactions they can activate or alter the function of various cell types, for example by inducing increased expression of adhesion molecules or increased cytokine production. Experimental data regarding these functions of platelet-, endothelial cell- and leukocyte-derived microparticles are summarized in the following paragraphs.
Platelet-derived microparticles contain arachidonic acid [137], which increases the adhesion of monocytes to endothelial cells by inducing upregulation of leukocyte function-associated antigen-1 and macrophage antigen-1 on the monocytes and ICAM-1 on the endothelial cells, and induces chemotaxis of monocytic U937 cells [138]. Furthermore, the arachidonic acid in the microparticles induces cyclooxygenase (COX)-2 expression as well as prostaglandin and thromboxane production in monocytic U937 cells [139], and COX-2 expression and prostacyclin production in endothelial cells [137]. Platelet-derived microparticles also contain and deliver the chemokine RANTES to activated or atherosclerotic endothelium, thereby promoting monocyte recruitment and arrest [140]. In addition, platelet-derived microparticles bind neutrophil granulocytes via P-selectin – sialyl LewisX interactions, resulting in aggregation and activation of these cells, as reflected by
increased CD11b expression and phagocytic activity [141]. Furthermore, platelet-derived microparticles can bridge leukocytes via P-selectin – PSGL-1 interactions under flow conditions [142], and alter the expression of several inflammatory genes in monocytic cells, as shown using DNA microarray technology [143].
Microparticles released from endothelial cells upon peroxide treatment contain oxidized phospholipids, which activate neutrophils via their receptor for platelet-activating factor (PAF), resulting in increased adhesion of these cells as assayed on a gelatin matrix [144]. Such microparticles also stimulate monocyte adhesion to endothelial cells in a PAF receptor-mediated process [145].
Microparticles released from activated leukocytes induce endothelial cell activation and the release of IL-6 and monocyte chemoattractant protein (MCP)-1 from these cells [105,146]. Also, microparticles released from activated T cells induce the synthesis of TNF and IL-1β in monocytes [147], and microparticles derived from T cells and monocytes induce the synthesis of matrix metalloproteinase-1, -3, -9, and -13 as well as IL-6, -8 and MCP-1 and -2 in fibroblasts [148]. Microparticles from synovial fluid of arthritis patients, mainly originating from granulocytes and monocytes, increase the synthesis of IL-6, -8, MCP-1, RANTES, ICAM-1 and vascular endothelial growth factor, and decrease the synthesis of granulocyte-macrophage colony-stimulating factor in synovial fibroblasts [149]. Also, microparticles derived from activated monocytic cells contain intravesicular, bioactive IL-1β, which they deliver to other cells and thereby activate their IL-1 receptors [150]. Furthermore, transfer of the chemokine receptor CCR5 between cells via cell-derived
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microparticles demonstrates that transfer of receptors may also represent a means by which microparticles can modulate inflammatory processes [151].
A second type of mechanism by which cell-derived microparticles might possibly contribute to inflammatory processes is activation of the complement system. In vitro, microparticles derived from apoptotic Jurkat cells or activated neutrophil granulocytes were found to bind complement component C1q and activate the classical pathway of complement, as shown by the deposition of downstream complement components C4 and C3 [152-154]. However, when comparing ex vivo microparticles isolated from plasma of healthy individuals and patients suffering from systemic lupus erythematosus, a disease in which complement activation plays an important pathogenic role, no differences were found in C1q binding [152]. The binding of other complement components was not analyzed, leaving the question whether cell-derived microparticles also play a role in complement activation in vivo unanswered.
Finally, cell-derived microparticles also have anti-inflammatory properties. Microparticles released from activated neutrophils, for example, do not activate human macrophages as assessed by their release of IL-8, -10 and TNFα, but increase their release of the anti-inflammatory cytokine transforming growth factor-β1 (TGFβ1). Furthermore, these microparticles decrease the production of IL-8, -10 and TNFα in the macrophages in response to stimuli such as LPS [155]. Additionally, microparticles derived from activated T cells induce the synthesis of the anti-inflammatory secreted IL-1 receptor antagonist in monocytes [147].
Other pathophysiological processes
Their have been several reports linking microparticles to other pathophysiological processes such as endothelium-dependent vasomotor dysfunction [156-160], transmission of infections [151,161], angiogenesis [162-168], tumor progression and metastasis [164,169-177], as well as cell survival and apoptosis induction [53,90,174,178]. The role of microparticles in these processes is partly a consequence of their inflammatory properties detailed above, but further discussion of these aspects of microparticle function is beyond the scope of this thesis.
Aims and outline of this thesis
As detailed above, over the past 60 years, and especially during the last 2 decades, countless studies have been performed to unravel the mechanisms behind the formation of cell-derived microparticles and to gain detailed knowledge regarding their composition and function in various disease states. The ultimate goal of these studies was to eventually find ways to modulate the processes in which microparticles are involved, to ameliorate certain diseases. However, many issues have still remained unresolved. The studies described in
this thesis therefore aim to further elucidate the composition of cell-derived microparticles as well as their role in coagulation and inflammation (in particular, complement activation) in various clinical conditions.
Section I
In Chapter 2, a contribution to a forum on measuring circulating cell-derived microparticles [179], the methods employed in our laboratory for blood collection and the initial processing and storage of samples for microparticle analyses are described, as well as our methods used for isolation and flow cytometric analysis of microparticles.
Section II
In the studies presented in this section, the composition and procoagulant properties of microparticles of various origin are investigated. In Chapter 3, platelet-derived microparticles obtained with various stimuli are compared with isolated platelet membrane fractions (plasma-, granule- and intracellular membranes) regarding their phospholipid composition and cholesterol content, to determine the origin of microparticle lipids, and to determine whether these lipids are sorted selectively into microparticles upon their formation and whether different stimuli result in different lipid compositions of the microparticles released from the same cell type. Furthermore, the exposure of activation markers on platelets and platelet-derived microparticles and their relation to the phospholipid content of the microparticles is determined. In Chapter 4, the thrombogenicity of cell-derived microparticles isolated from human blood is investigated for the first time in an in vivo thrombosis model, and the role of TF exposed on the microparticles is determined herein. In Chapter 5, the phospholipid composition of endothelial cell-derived microparticles released from resting or IL-1α-stimulated cells is analyzed. Furthermore, the thrombogenicity of these microparticles and the role of TF herein is determined in the in vivo thrombosis model also used in Chapter 4. In Chapter 6, the relationship between the activation status of platelets, assessed by the analysis of their exposure of the activation markers P-selectin and CD63, and the numbers and P-selectin and CD63 exposure of the microparticles released from them upon in vitro stimulation is determined. (CD63 is a member of the tetraspanin superfamily present in the lysosomal- and dense granule membranes of resting platelets, and exposed on the platelet surface upon exocytosis of the respective granules [180,181].) Subsequently, the concentrations of platelet-derived microparticles circulating in vivo and the percentages exposing P-selectin or CD63 are measured in young and older healthy individuals and patients suffering from cardiovascular diseases, as a reflection of the platelet activation status in vivo in these conditions. In Chapter 7, to try and clarify existing inconsistencies in the literature regarding the role of coagulation, platelet and endothelial cell activation and fibrinolysis in Fabry disease, markers of these processes as well as their possible association with
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circulating microparticles are analyzed in these patients, also taking into consideration the severity of the disease and renal function.
Section III
In the studies described in this section, the complement activating properties of microparticles are investigated in various clinical conditions. First, in Chapter 8, a brief overview of the complement system is given, and data supporting the pathogenic role of the complement system in rheumatoid arthritis (RA) are reviewed, as well as therapeutic advances aimed at influencing the complement system in this disease. Subsequently, in
Chapter 9, microparticles from synovial fluid and plasma of RA patients and plasma of
healthy individuals are analyzed for bound complement components and complement activator molecules, to investigate whether complement activation occurs on the surface of these microparticles in vivo. In Chapter 10, microparticles isolated from pericardial wound blood of patients undergoing cardiac surgery with CPB are analyzed to determine whether they contribute to complement activation in pericardial blood. Furthermore, the effect of retransfusion of pericardial blood on systemic complement activation is studied. In
Chapter 11, the possible role of microparticles in complement activation in patients with
myocardial infarction is investigated. Finally, in Chapter 12, the possible role of microparticles in complement activation in preeclamptic and healthy pregnant women is analyzed.
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