[Frontiers in Bioscience 14, 4932-4949, June 1, 2009]
Heparan sulfate proteoglycans in extravasation: assisting leukocyte guidance
Johanna W.A.M. Celie1, Robert H.J. Beelen1, Jacob van den Born2
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TABLE OF CONTENTS
1. ABSTRACT
Heparan sulfate proteoglycans (HSPGs) are glycoconjugates that are implicated in various biological processes including development, inflammation and repair, which is based on their capacity to bind and present several proteins via their carbohydrate side chains (glycosaminoglycans; GAGs). Well-known HSPGs include the family of syndecans and glypicans, which are expressed on the plasma membrane and perlecan, agrin and collagen type XVIII, which are present in basement membranes. In this review, we provide an overview of the current knowledge on the role and regulation of HSPGs in leukocyte extravasation. In the non-inflamed endothelial glycocalyx HSPGs are anti-adhesive, and there are several indications that active regulation of HSPG core protein expression and/or GAG modification occurs upon inflammation. We address the current evidence for the role of HSPGs in leukocyte extravasation through interaction with the leukocyte adhesion molecule L-selectin, chemokines and other binding partners. Finally, a number of possibilities to use HSPGs as therapeutics or targets in anti-inflammatory strategies are discussed.
2. INTRODUCTION
Upon inflammation, leukocytes migrate from the bloodstream through the vessel wall towards the site of inflammation. The process of leukocyte transendothelial migration involves several sequentially acting molecules. The complexity of this system prevents inappropriate inflammatory responses, and enables combinatorial specificity (1). The multistep paradigm of leukocyte transmigration initially comprised leukocyte rolling (step 1), activation (step 2), firm adhesion (step 3) and transmigration (step 4) (2,3). However, the original paradigm has been expanded and modified based on new findings (1,4,5). The involvement of the family of heparan sulfate proteoglycans (HSPGs) at multiple levels in this process is becoming increasingly clear. The vast majority of functions ascribed to HSPGs depends on their ability to bind different cytokines, chemokines, growth factors and the leukocyte adhesion molecule L-selectin. This review describes our current knowledge of the role of HSPGs in leukocyte extravasation and trafficking, regulation of their expression and binding properties, and a number of possibilities to use HSPGs as therapeutic agents or targets in anti-inflammatory strategies.
3. HSPG STRUCTURE, BIOSYNTHESIS AND PROTEIN BINDING PROPERTIES
Proteoglycans consist of a core protein to which extended linear carbohydrate chains (glycosaminoglycans; GAGs) are attached (Figure 1A). Based on the GAG-composition, proteoglycans are divided in different types, being heparan sulfate (HS), chondroitin sulfate (CS), dermatan sulfate (DS), or keratan sulfate (KS) (6,7). Proteoglycans are not to be confused with N-linked glycoproteins, which bear relatively short, branched carbohydrate structures containing mannose, fucose and sialic acid residues.
HSPGs are expressed on the cell surface and in the extracellular matrix (ECM). Based on their core proteins, the majority of cell-surface HSPG belong to the family of syndecans or glypicans (Figure 1A). Four mammalian syndecans are known (syndecan-1 to -4), which are transmembrane molecules with typically three to five HS-chains, although also CS/DS-chains can be attached to syndecan core proteins (8,9). Glypicans are linked to the cell surface by a glycosylphosphatidylinositol anchor, and six mammalian glypicans have been described (glypican-1 to -6) (10). Syndecan HS-chains are located distal from the plasma membrane, whereas glypican HS-chains are located close to the membrane (Figure 1A). Apart from syndecans and glypicans, also 'part-time' cell surface HSPGs are known, e.g. CD44 and betaglycan (11,12). ECM HSPGs include agrin, perlecan and collagen type XVIII, which are typically found in basement membranes (13,14). Another familiar molecule in this context is the pharmaceutical heparin, which is a highly sulfated free HS-chain that contains a high amount of iduronic acid. Heparin is only attached to a core protein (serglycin) inside the granules of its producing cell, the mast cell (15).
HSPGs are very heterogeneous molecules based on the large variation in their HS-chain composition. HS-chains are initially synthesized as alternating glucuronic acid (GlcA) and N-acetylglucosamine (GlcNAc) residues (Figure 1B). These residues can subsequently be modified by the coordinated action of various enzymes, resulting in varying degrees of sulfation (N-sulfation and O-sulfation at various positions) and epimerization (converting GlcA to iduronic acid) (Figure 1B). Several isotypes have been identified for many HS modifying enzymes, adding to the complexity of the system. Theoretically, over 20 differently modified disaccharide units can be synthesized, and their combined diversity can result in highly heterogeneous HS-chains, which can all encode a different 'message'. Typically however, HS-chains are organized in highly modified domains with high N-sulfation (NS), O-sulfation and iduronic acid content, flanked by moderately modified (NA/NS) domains, interspersed with stretches of unmodified (NA) domains (Figure 1C). For further description of HS-biosynthesis we refer to excellent reviews on this topic (16-18).
As mentioned above, HSPGs are able to bind various cytokines, chemokines, growth factors and L-selectin through their HS-chains. Interestingly, different HSPG binding partners tend to require somewhat different GAG modification for binding (16,17,19). Important determinants for binding include degree and position of GAG-chain sulfation, epimerization, but also 3D-conformation (20,21). Therefore, differences in HS-chain fine-structure could affect the function of HSPGs and their binding partners in certain locations and under certain conditions, including inflammation.
4. HSPGS ON THE ENDOTHELIUM - STICKY OR NOT
4.1. Anti-adhesive HSPGs in the non-inflamed endothelial glycocalyx
Under non-inflamed conditions, the endothelial surface is covered with a relatively thick sheath of glycosylated molecules, referred to as the glycocalyx (22,23). HS is regarded to be the dominant GAG within the glycocalyx, although also CS/DSPGs and hyaluronic acid are present, and relative amounts can differ between different endothelial cell preparations (22). Together with sialylated glycoproteins, HSPGs are partly responsible for conferring the negative charge to the glycocalyx (Figure 2A) (22). In the absence of an inflammatory insult, the endothelial glycocalyx serves as an anti-thrombotic, anti-proliferative, and anti-inflammatory sheath. These actions are likely to depend both on masking of the underlying endothelial plasma membrane and its associated molecules, and on charge repulsion (both glycocalyx and leukocyte cell surface are negatively charged) (23). Upon inflammation, (part of) the glycocalyx can be shed, facilitating cell-cell interactions by reducing negative charge, and exposing underlying and newly synthesized molecules (Figure 2B) (22,24-27). Interest in the role of HSPGs in the endothelial glycocalyx has increased over the last few years and has been subject of several independent studies. Injection of heparitinase I (which specifically degrades HS) into mouse cremaster muscle venules increased the number of adherent leukocytes, indicating that HS in non-inflamed venules is anti-adhesive (28). Interestingly, Ox-LDL also induced degradation of the glycocalyx and increased adhesion of leukocytes (28). This effect could be inhibited by HS/heparin, which were bound to the luminal side of the endothelium, likely reflecting reconstitution into the degraded glycocalyx (28). These results suggest that changes in the glycocalyx, and its HSPGs, may play a role in atherothrombosis and -sclerosis (23,29). In addition, HSPGs were shown to function as endothelial sensors of blood flow (30,31), which may also play a role in atherosclerosis (local perturbations in blood flow) as well as other types of inflammation (e.g. reduced blood flow due to vasodilatation and endothelial swelling). In turn, recent studies show shear-dependent alterations in glycocalyx composition (23).
Although various studies show that the endothelial glycocalyx is (at least partly) shed upon inflammation, both shedding and increased exposure of one of its components, syndecan-1, has been reported in inflammatory settings (24,25,32). This apparent contradiction may be due to differences in glycocalyx composition in cultured cells compared to in vivo, inflammatory stimuli, and possibly vascular beds. It is however an important point, as the presence of a particular HSPG at the inflamed endothelium dictates whether it can be involved in leukocyte extravasation.
- HSPGs on the inflamed endothelium: interaction with L-selectin
The first phase of transendothelial migration is defined as selectin-mediated 'rolling' of the leukocyte over activated endothelium. E- and P-selectin are expressed on activated endothelium (as well as on platelets for P-selectin), whereas L-selectin is constitutively expressed on leukocytes. All three selectins bind glycoproteins decorated with (sulfated) sialyl Lewisx residues (33,34). In addition, binding of P- and especially L-selectin to HSPGs is now established, whereas binding of E-selectin to HSPGs remains controversial (35-40). Sulfation of HS is critical for both P- and L-selectin binding, and heparinoids inhibit inflammation by blocking P- and L-selectin activity (38,39,41). However, if endogenous HSPGs are involved in leukocyte transmigration in vivo, it should be possible to demonstrate P-selectin binding HSPGs on leukocytes (section 7) and/or L-selectin binding HSPGs on inflamed endothelium. Several groups have shown binding of recombinant L-selectin to HSPGs expressed by cultured endothelial cells intracellularly (42), associated with the cell-surface and/or ECM, or in the culture medium (43,44). Support for a functional role of the interaction between L-selectin and HSPGs is provided by Wang et al. who elegantly showed that reducing endothelial HS sulfation by inactivating N-deacetylase N-sulfotransferase-1 (NDST-1) impairs neutrophil extravasation (45). This could be partially explained by reduced binding of L-selectin to NDST-1-deficient endothelial cells in vitro, resulting in increased neutrophil rolling velocity and reduced firm adhesion. Similarly, leukocyte rolling and adhesion to endothelial cells of different origins is reduced after enzymatic removal of HS, or by antibodies that target N- and 6-O-sulfated HS domains (44,46,47). Interestingly, there are clear indications that HSPGs are not only involved in leukocyte-endothelial interactions, but also in adhesion of hematopoietic progenitor cells to bone marrow endothelial cells (48). Adhesion of progenitor cells was reduced when the bone marrow endothelial cells were cultured in the presence of chlorate, which inhibits GAG-chain sulfation, and by enzymatic removal of HS (48). Blocking studies indicated L-selectin to be one of the binding partners involved (48).
Although several studies describe a role for the interaction between L-selectin and endothelial HSPGs in leukocyte transmigration (Figure 2B), to our knowledge no single HSPG expressed on the endothelial cell surface has yet been identified as direct ligand for L-selectin. Endothelial syndecans have been proposed as likely candidates, although also glypicans, and the part-time HSPG CD44 can be considered (49-53). Examination of L-selectin ligands in situ using recombinant L-selectin proteins as probes has been performed, predominantly in various types of renal inflammation (54-56). In the non-inflamed kidney, L-selectin binding HSPGs are present in tubular basement membranes, but not associated with the endothelium (41,57-59). In both experimental and human renal inflammation tissues, L-selectin binding HSPGs are detected at the abluminal side of peritubular capillaries (but not at the endothelial surface), and these HSPGs are likely to be perlecan, collagen type XVIII and/or agrin (55,56). Mice deficient for perlecan-HS and collagen type XVIII showed reduced/delayed inflammation-induced monocyte influx, and the induction of perivascular L-selectin binding HSPGs in human renal biopsies correlates with increased leukocyte counts, indicating that these subendothelial HSPGs do contribute to leukocyte extravasation (55,56). Possibly, inflammation-induced endothelial damage exposes the vascular basement membrane components to leukocytes. Formally it cannot be excluded that L-selectin binding HSPGs are expressed on the luminal side of endothelial cells in these settings, as levels may be too low for detection or binding sites may be masked by plasma proteins adsorbed to HS. However, a recent study in mouse cremaster muscle venules, commonly used to study leukocyte rolling, has doubted whether L-selectin ligands are expressed at all at the luminal side of endothelial cells, as L-selectin coated beads did not significantly adhere to the endothelium but rather to adherent leukocytes (60). In this study, L-selectin mediated rolling was completely explained by secondary tethering (rolling of leukocytes over adherent leukocytes) (60). In parallel, wildtype and L-selectin knockout mice showed similar leukocyte rolling, although extravasation and extravascular locomotion was reduced in L-selectin knockout mice (61). An interesting possibility is that HSPGs do not (only) function as adhesive ligands for leukocytes via L-selectin, but may (also) activate transmigrating leukocytes via the same molecule (Figure 2B). L-selectin cross-linking was shown to activate leukocytes (62,63), and the repetitive HS domain structure could be a likely candidate to cause L-selectin cross-linking.
Summarizing, there is compelling evidence indicating that an interaction between L-selectin and vascular HSPGs enhances leukocyte extravasation, although the exact mechanism deserves additional research.
4.3. Other adhesive interactions with endothelial HSPGs
Apart from L-selectin, other leukocyte adhesion molecules have been shown to interact with HSPGs, thereby potentially affecting extravasation. Especially the interaction between HSPGs and integrins is interesting in this respect. Binding of leukocyte-expressed integrin Mac-1 (CD11b/CD18) to HS has been demonstrated years ago, and this interaction was shown to cause firm adhesion after initial rolling over P/E-selectin under flow (64,65). Also binding of HSPGs to other adhesion molecules, including CD45 and CD31 (PECAM-1) has been reported, although the functional relevance of these interactions is unclear (65-67). Interestingly, mammalian heparanase, which is mainly known to degrade HS at low pH (section 6), can in its inactive form also induce T-cell adhesion under shear flow conditions, although the exact mechanism remains to be determined (68).
5. HSPGS AND CHEMOKINES: SELECTIVE PRESENTATION
5.1. HSPGs present chemokines to facilitate directional migration
In the second step of transmigration, binding of chemokines to high-affinity receptors on leukocytes causes integrin activation and firm adhesion (69). Both cell-surface and extracellular matrix HSPGs can bind chemokines via their HS-chains (Figure 2B). In this way, chemokines are retained locally, prevented from degradation (70), and presented to leukocytes. In addition, chemokines bound to HSPGs may serve as local storage depots, or could be functionally scavenged away (69). Interestingly, both chemokines and HS show a certain amount of specificity in their interaction. Different chemokines use different protein domains for their binding to HS, which may confer HS-chain selectivity, and has even been suggested to potentially control chemokine receptor selectivity (71,72). HS-chains in turn have different sulfation patterns favoring binding of certain chemokines over others, which may help attract different leukocyte subsets (73). This mutual selectivity can offer another level of regulation of chemokine function, which is thereby determined by cells producing the chemokine as well as their environment (74).
The notion that chemokine binding to GAGs is important for leukocyte extravasation has been elegantly demonstrated using GAG-binding mutant chemokines, which can bind and activate their high-affinity receptors, but have mutated GAG-binding domains. For example, monocyte transmigration was significantly reduced using GAG-binding mutant CCL5/RANTES compared to the wildtype chemokine (75). Similarly, experiments using GAG-binding mutant CCL2/MCP-1 and CCL4/MIP-1beta show a reduction in leukocyte transendothelial migration in vitro, and leukocyte emigration towards the peritoneal cavity in vivo (75-77).
5.2. Chemokine presentation by HSPGs at the endothelial surface
Chemokines are considered to bind to luminal endothelial cell proteoglycans to prevent them from being washed away by blood flow and to enhance clustered presentation (78-80). A number of studies have shown HS-mediated binding of chemokines to the luminal surface of (activated) endothelial cells (81-83). Dermally injected CXCL8/IL-8 was shown to localize to postcapillary venules and small veins, where it is internalized abluminally by endothelial cells, transcytosed to the luminal surface, and presented on endothelial cell projections (83). Importantly, the heparin binding domain of CXCL8/IL-8 is necessary for binding and transcytosis, and in vivo activity of the chemokine (83). In line with these findings, binding and transcytosis of CXCL8/IL-8 was significantly impaired in endothelial cells with reduced HS sulfation due to NDST-1 inactivation (45). Hardi et al. showed that exogenously added CCL2/MCP-1 is presented apically on endothelial-like cells in a clustered fashion, although HS was present all over the cell surface, indicating preferential binding to a certain HSPG or HS-domain (82). This again stresses that endothelial cells may not necessarily bind a particular chemokine even though they express HSPGs, based on HS-chain dependent selectivity (55,73).
Chemokine binding at the endothelial lumen is generally considered to be mediated by syndecans, although only a limited number of studies show an actual interaction between syndecans and chemokines. Syndecan-1 and/or -2 derived from human umbilical vein endothelial cells were shown to bind CXCL8/IL-8 (32,84). Syndecan-3 was proposed as the dominant HSPG to bind the same chemokine on inflamed synovial endothelium (85). As HSPG core protein expression and HS-chain modification may be different in various vascular beds, it would be interesting to examine more specifically which endothelial HSPGs bind and present which chemokines under inflammatory conditions in situ (e.g. in tissue sections) (80).
Apart from presentation of chemokines at the endothelial lumen, it has been suggested that (HS)PG-generated concentration gradients across the endothelium could be important for leukocyte extravasation (79). To our knowledge, a concentration gradient of chemokine in between endothelial cells has not been demonstrated (82). It seems more likely that the presence of immobilized chemokine on one side of the leukocyte would be sufficient to polarize the leukocyte and thereby direct migration (86).
6. BEYOND THE ENDOTHELIUM: HSPGS IN THE VASCULAR BASEMENT MEMBRANE
After passing the endothelial cell layer, extravasating leukocytes encounter the vascular basement membrane. This membrane consists of a dense network of ECM proteins, providing stability to the vascular structure. Leukocyte migration through this barrier is considered to involve local degradation of matrix molecules by specific enzymes, including matrix metalloproteinases (MMPs) and ectoenzymes (87), although specific matrix protein low expression regions have also been identified as preferential exit points for neutrophils (1,88,89).
HSPGs are vascular basement membrane components that help provide structural stability (14). In addition and as described above, subendothelial HSPGs can bind chemokines and L-selectin under inflammatory conditions (55,90), which may enhance extravasation, as well as directed migration by the formation of a haptotactic gradient (91). Cleavage of HSPGs is considered to be necessary for leukocyte migration through the subendothelial matrix (Figure 2C). Leukocytes, endothelial cells and platelets express the HS-specific endoglycosidase heparanase (92-96). Heparanase acts at pH 6 but not at physiologic pH, is resistant to protease activity, and is relocated to the leading edge of migrating leukocytes, supporting its role in HS degradation at the site of inflammation (92,95,97-99). This enzyme specifically cleaves HS-chains within a sequence that has not been defined completely yet, resulting in HS fragments of 10-20 carbohydrate units that retain biological activity (96,98,100). Inhibition of heparanase activity by a polysulfated polysaccharide was shown to inhibit experimental autoimmune encephalitis, although this compound likely interfered with other processes involved in leukocyte extravasation apart from heparanase activity alone (101). The role of heparanase in extravasation has been demonstrated more specifically by Edovitsky et al, who locally administrated siRNA to target endothelial heparanase, resulting in decreased delayed-type hypersensitivity inflammatory response in vivo (102). Apart from heparanase, leukocytes can also produce reactive oxygen species (ROS), which can cause HS depolymerization (103-105). However, to our knowledge the importance of ROS-induced HS degradation in leukocyte extravasation has not been shown to date.
Degradation of subendothelial HS could both loosen the matrix to facilitate leukocyte migration, and release locally bound cytokines and chemokines, which can affect cell migration and/or activation (106). Interestingly, fragments of several extracellular matrix proteins have also been shown to activate immune cells directly via interaction with toll like receptors (TLRs), which may function to monitor tissue damage. For example, soluble HS can bind TLR-4 on dendritic cells, which results in dendritic cell maturation (7,107). In addition, HS/heparin di/trisaccharides have been shown to affect T-cell intracellular signaling, adhesion and migration, as well as macrophage function (108-111). The combined roles of ECM HSPGs could thereby significantly influence the inflammatory response, both at the level of cell migration and activation.
7. HSPGS ON LEUKOCYTES
Apart from the endothelium, also leukocytes express HSPGs (112-117). Leukocyte HSPGs may influence transendothelial migration by interacting with P-selectin, or by presenting chemokines to their high affinity receptor in a trimolecular complex on the leukocyte cell surface (in cis). However, no leukocyte-expressed HSPG that binds P-selectin has been reported to date. In addition, GAG-binding mutant chemokines which lack GAG-binding capacity can still efficiently signal through their chemokine receptor and induce chemotaxis in a free diffusion solute gradient, suggesting that presentation of chemokines by HSPGs in cis is not of major importance (76,118,119). However, there are studies indicating that binding of chemokines to cell surface HSPGs could directly result in intracellular signaling, independent of G-protein coupled chemokine receptors, as shown for CCL5/RANTES and CD44 (120,121). In addition, T-cell adhesion and migration was shown to be triggered by binding of cyclophilin B to syndecan-1 HS, which enhances syndecan-1 association with CD147 and subsequent intracellular signalling (117,122,123).
In vitro, transendothelial migration was reduced when monocytes were cultured in the presence of chlorate (inhibiting GAG sulfation) or upon treatment with heparitinase (specifically degrading HS) (124). Evidence for a role of leukocyte HSPGs in extravasation in vivo has come from syndecan-1 deficient mice, which display increased leukocyte-endothelial adhesion in the ocular vasculature (125). This appeared to contradict the proposed role of HSPGs (including syndecan-1) in enhancing leukocyte rolling and adhesion, but the effect was shown to be mostly due to the lack of syndecan-1 on leukocytes (125,126). Similarly, leukocyte recruitment was increased in syndecan-1 deficient mice in both experimental anti-glomerular basement membrane nephritis, and myocardial infarction (127,128). In the latter, systemic adenoviral overexpression of syndecan-1 reduced the number of inflammatory cells in the infarct area (128). Together, these studies indicate that leukocyte-expressed syndecan-1 can inhibit extravasation, possibly by scavenging chemokines, masking or competing for interactions with adhesion molecules, or simply by increasing cellular negative charge, thereby inhibiting cell-cell interactions. However, the observation that leukocyte extravasation was not affected by inactivation of NDST-1 in leukocytes indicates that leukocyte HS sulfation is of lesser importance for leukocyte extravasation, although it may play a role in T-cell activation (45,129). An alternative explanation for the increased adhesion of syndecan-1 deficient leukocytes could be that the lack of syndecan-1 affects leukocyte adhesion by influencing integrin activation, as functional cooperation between syndecans and integrins in cis (on the same cell) has been shown to enhance cell adhesion due to cross-talk in intracellular signaling pathways (130).
8. REGULATION OF HSPGS UPON INFLAMMATION
8.1. Regulation of core protein expression
As HSPGs are constitutively present on the cell surface and in the ECM, regulation of expression and/or binding capacities (section 8.2) of these molecules upon inflammation seems likely (data described below are summarized in Figure 3). Regulation of syndecan core protein expression has been studied most extensively (49,131). In vitro, upregulation of syndecan-1, -2 and -4, glypican-1 and the part-time HSPG CD44 has been shown on cultured endothelial cells stimulated with pro-inflammatory cytokines TNF-alpha and/or IL-1beta (47,84,132). In vivo, syndecan-1 expression is induced in endothelial cells that revascularize healing wounds and in myocard infarct areas (128,133,134). In addition, endothelial syndecan-3 staining was increased, whereas syndecan-2 and glypican-1 and -4 staining was detected but not different, in inflamed compared to non-inflamed synovium (51,85).
Several studies indicate that syndecan core protein expression can be regulated by the pro-inflammatory NF-kappaB pathway (132,135). In addition, the syndecan-1 gene contains an FGF-inducible response element upstream from the promotor region, which appears to act as an enhancer of transcription (136-138). This clearly implicates regulation of syndecan-1 in inflammation and repair. Interestingly, several HSPGs also have putative target regions for microRNAs ( (139) and Celie, unpublished observation (Sanger microRNA database (http://microrna.sanger.ac.uk)), which are small non-coding RNA sequences that can regulate protein expression by inhibiting mRNA translation (140).
In addition to regulation of transcription/translation, syndecans are susceptible to ectodomain shedding, which can affect their function. For example, human umbilical vein endothelial cells constitutively shed syndecan-1/IL-8 complexes under the influence of plasmin under culture conditions (32). This shedding can be inhibited by endothelial PAI-1, which appears to stabilize the syndecan-1/IL8 complex at the cell surface, facilitating neutrophil transmigration (32). Thrombin and EGF were shown to enhance endothelial syndecan-1 and -4 shedding (141). In contrast to stabilizing chemokine/HSPG complexes on the endothelial surface to enhance transmigration, MMP-7 induced shedding of syndecan-1/KC complexes directs transepithelial efflux of neutrophils in the inflamed lung (142). Interestingly, heparanase was also shown to induce syndecan-1 shedding in multiple myeloma and breast cancer cells, and silencing of heparanase gene expression down-regulated syndecan-1 mRNA (143,144). Future studies will further clarify the regulatory pathways involved in HSPG core protein expression upon inflammation.
8.2. Regulation of HS biosynthesis & modification; changes that affect chemokine/L-selectin binding
Regulation of HS biosynthesis and modification can have important effects on HSPG binding capacity, including binding to chemokines and L-selectin. GAG-chain sulfation is an important determinant for both, and there is evidence showing that HS sulfation is altered upon inflammation. NDST-1 and -2 mRNA levels were transiently decreased in microvascular endothelial cells at 4 hours of IFN-gamma or TNF-alpha stimulation, followed by an increase in NDST-1 expression at 16 hours (81). Binding of CCL5/RANTES to the endothelial cells, and transendothelial leukocyte migration paralleled the increase in NDST-1 expression (81). Similarly, TNF-α stimulation was shown to lead to an NF-kappaB-dependent increase in NDST-1 and -2, and 6-O-sulfotransferase-1 and -2 mRNA in glomerular endothelial cells (47). In the same cells expression of endo-6-O-sulfatase-2 (Sulf2) was decreased, whereas heparanase was increased, suggesting a shift towards more N- and 6-O-sulfated HS fragments (47). Increased HS-dependent binding of L-selectin and chemokines to endothelial cells has been shown upon stimulation in vitro, or when cells are derived from inflamed tissue (44,145). As described above, inflammation-induced L-selectin and chemokine binding to subendothelial HSPGs has been shown in situ in synovial tissue and the kidney (55,85,90). This may be at least partially due to modification of HS fine-structure, as no changes in core protein expression could be detected (55). Indeed, increased HS-mediated subendothelial binding of L-selectin and CCL2/MCP-1 coincided with reduced endothelial expression of the extracellular 6-O-sulfatase HSulf-1in acute renal allograft rejection (55). Although changes in expression of HSulf-2 were not detected in this study, this enzyme also has the potential to affect chemokine binding (146). Interestingly, mRNA for PAPS transporter, which transports sulfate-donors into the Golgi for use by various sulfotransferases, is increased in capillaries in both experimental heart and kidney transplantation-induced acute inflammation (147). Apart from inflammation, HSPGs have also been implicated in transendothelial migration of stem cells to the bone marrow, via presentation of the stem cell chemokine stromal derived factor-1 and adhesive interaction with L-selectin (48,91,148). Interestingly, bone marrow endothelial cells were shown to express more highly sulfated HS than human umbilical vein endothelial cells, favoring both chemokine and L-selectin binding (149). Studies into the transcriptional regulation of HS biosynthetic enzymes involved, and resulting GAG-chain properties, would be interesting to gain more insight into the formation of these apparently constitutive 'extravasation-enhancing' HS-types.
In the recent years, interest has focused on the notion that not only HS sulfation, but also the resulting 3D-conformation of HS-chains, spatially positioning certain sulfate groups in more or less flexible regions of the GAG-chain, is important in determining binding activity and specificity (20,150,151). In addition, environmental factors, including pH and the presence of particular cations (including Zn2+ contained in platelets), can contribute to HS-chain conformation and/or binding properties, making the situation even more interesting, but also even more complex (21,151).
9. HSPGS AS THERAPEUTICS OR TARGETS IN ANTI-INFLAMMATORY STRATEGIES
Based on the variety of functions of HSPGs, these molecules could be interesting therapeutic agents, or possibly targets, in anti-inflammatory strategies (Table 1). This would be especially relevant in chronic inflammation and auto-immune diseases (e.g. artherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis). Other situations in which HSPGs are considered as therapeutic agents or targets include oncology, especially focusing on the potential of inhibiting growth factor signaling, angiogenesis and heparanase-induced degradation of ECM by tumor cells, which precedes metastasis (152-154). Heparin has been shown to bind and inhibit several molecules involved in leukocyte extravasation, including selectins, chemokines, leukocyte integrins, and heparanase (36,39,40,46,64,96,99,155), which can likely explain the anti-inflammatory effects observed after (low molecular weight) heparin administration in various models (Table 1). Interestingly, also tumor cells have been shown to exploit integrin- and selectin-mediated adhesion during metastasis (156-158). Nowadays, interest is focusing on the possibility to produce small HS-mimetics, which may more specifically target a particular component of HS/heparin bioactivity (154,159). For this, it will be necessary to obtain pure, homogeneous oligosaccharide preparations, which can probably only be achieved by chemical synthesis. This approach has proven particularly challenging, but significant progress has been made in the last years, for example by the generation of heparin-glycan arrays to study heparin-protein interactions and the production and clinical use of Fondaparinux (synthetic heparin-like pentasaccharide) (73,160-163). Factors known to potentially influence the biological activity of these compounds, including multivalent linkage and 3D conformation, may be taken into consideration to find a balance between biostability, activity and specificity.
The use of HSPGs as targets, for example using antibodies that recognize and thereby block specific HS-motifs/domains, may also have clinical potential. This strategy has been exemplified in vitro by the demonstration that 6-O-sulfate specific anti-HS antibodies produced in a phage-display library can inhibit leukocyte rolling and firm adhesion to glomerular endothelial cells, whereas anti-HS antibodies with different specificities do not (47). GAG-binding deficient chemokines can be used to specifically inhibit cell migration (164). In addition, small inactive chemokine fragments can be generated that block the HSPG-binding sites of their in vivo active counterparts (164). Together, there are many options for the use of HSPGs in therapeutic strategies, although many need further development and proof of efficacy in vivo.
10. CONCLUSIONS & PERSPECTIVES
In this review, we have described the current knowledge regarding the role and regulation of HSPGs in different steps of leukocyte extravasation. There are clear indications to show that in the non-inflamed endothelial glycocalyx HSPGs have anti-adhesive properties, whereas endothelial HSPGs can promote leukocyte extravasation upon inflammation through their interaction with different proteins, including L-selectin and chemokines. This may be explained by the observation that upon inflammation (part of) the anti-adhesive endothelial glycocalyx is shed. Theoretically, it is possible that pro-adhesive HSPGs are continuously expressed but masked by the glycocalyx, although this seems unlikely as the cellular machinery for HS synthesis and modification is considered to be shared by all HSPGs expressed by a certain cell, which should result in similar HS profiles. Accumulating evidence shows inflammation-induced changes at the level of core protein synthesis, but importantly also of HS-chain modification, which may account for the change in HSPG properties from anti-adhesive to pro-inflammatory. Possibly, changes in HSPGs over time can help define and contain the inflammatory response, affecting the type of leukocyte that extravasates (71,72), the vascular bed through which extravasation occurs (165), and the transition from acute to chronic (or resolution of) inflammation. Interestingly, chemokine-induced leukocyte migration can be inhibited by the family Slit-proteins, and these proteins have been shown to bind HS (166-169). Emerging in vivo experiments show that Slit-proteins can inhibit leukocyte infiltration in various inflammatory models (170,171). Further research may direct at these topics, e.g. specifically examining HSPG binding properties or HS modification at different timepoints and under different inflammatory conditions. In addition, it would be interesting to examine whether HSPG subsets are located in membrane domains, where they may function to enhance the interaction between endothelial cell and leukocyte. A remaining challenge in this context is to prove causality between changes in expression of HSPG core proteins/modifying enzymes based on the high potential for redundancy (multiple core proteins as well as modifying enzymes) and post-translational regulation (enzyme activity, shedding of core proteins). In addition, HSPGs are known to be important in development and structural stability of tissues, and therefore tissue-specific and/or inducible knockout animals for different core proteins and/or modifying enzymes may significantly contribute to our understanding of the role of HSPGs in specific settings.
Interestingly, HSPG binding properties may not only play a role at the endothelial surface but also in the underlying vascular basement membrane, affecting directional cell migration and activation. Degradation of HS by heparanase can both allow cell migration through this barrier and release bioactive HS fragments. The ability to interfere specifically with any of the above-mentioned roles of HSPGs may have significant therapeutic implications, and considerable effort is being invested in this direction. Typically, HS modifying reactions do not go to completion in vivo, and it would be interesting to consider the existence of inhibitors of the modifying enzymes in vivo, either at the transcriptional or translational level, or the development of compounds that block or skew away from a particular (undesired) reaction.
In conclusion, there is compelling evidence that HSPGs play an important role in leukocyte extravasation. Future studies of the mechanisms, regulation and specificity of HSPG-mediated interactions in different inflammatory reponses will further increase our understanding of these intricate but intriguing molecules, and can open important new therapeutic possibilities.
11. ACKNOWLEDGMENTS
The work of J.W.A.M. Celie is supported by grant C06.2163 from the Dutch Kidney Foundation.
12. REFERENCES
1. Ley K., C. Laudanna, M.I. Cybulsky, S. Nourshargh: Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7, 678-689 (2007)
doi:10.1038/nri2156
2. Butcher E.C.: Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 67, 1033-1036 (1991)
doi:10.1016/0092-8674(91)90279-8
3. Springer T.A.: Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76, 301-314 (1994)
doi:10.1016/0092-8674(94)90337-9
4. Pober J.S., W.C. Sessa: Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7, 803-815 (2007)
doi:10.1038/nri2171
5. Sackstein R.: The lymphocyte homing receptors: gatekeepers of the multistep paradigm. Curr Opin Hematol 12, 444-450 (2005)
doi:10.1097/01.moh.0000177827.78280.79
6. Prydz K. and Dalen, K. T.:Synthesis and sorting of proteoglycans. J.Cell Science 113, 193-205 (2000)
No DOI Found
7. Taylor K.R., R.L. Gallo: Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. FASEB J 20, 9-22 (2006)
doi:10.1096/fj.05-4682rev
8. Bernfield M., M. Götte, P.W. Park, O. Reizes, M.L. Fitzgerald, J. Lincecum, M. Zako: Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68, 729-777 (1999)
doi:10.1146/annurev.biochem.68.1.729
9. Carey D. J.: Syndecans: multifunctional cell-surface co-receptors. Biochem J 327 (Pt 1),1-16 (1997)
No DOI Found
10. Filmus J., S.B. Selleck: Glypicans: proteoglycans with a surprise. J Clin Invest 108, 497-501 (2001)
No DOI Found
11. Barbour A.P., J.A. Reeder, M.D. Walsh, J. Fawcett, T.M. Antalis, D.C. Gotley: Expression of the CD44v2-10 isoform confers a metastatic phenotype: importance of the heparan sulfate attachment site CD44v3. Cancer Res 63, 887-892 (2003)
No DOI Found
12. Eickelberg O., M. Centrella, M. Reiss, M. Kashgarian, R.G. Wells: Betaglycan inhibits TGF-beta signaling by preventing type I-type II receptor complex formation. Glycosaminoglycan modifications alter betaglycan function. J Biol Chem 277, 823-829 (2002)
doi:10.1074/jbc.M105110200
13. Iozzo R.V.: Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem 67, 609-652 (1998)
doi:10.1146/annurev.biochem.67.1.609
14. Iozzo R.V.: Basement membrane proteoglycans: from cellar to ceiling. Nat Rev Mol Cell Biol 6, 646-656 (2005)
doi:10.1038/nrm1702
15. Kolset S.O. and H. Tveit: Serglycin--structure and biology. Cell Mol Life Sci 65, 1073-1085 (2008)
doi:10.1007/s00018-007-7455-6
16. Esko J.D., S.B. Selleck: Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem 71, 435-471 (2002)
doi:10.1146/annurev.biochem.71.110601.135458
17. Kreuger J., D. Spillmann, J.P. Li, U. Lindahl: Interactions between heparan sulfate and proteins: the concept of specificity. J Cell Biol 174, 323-327 (2006)
doi:10.1083/jcb.200604035
18. Esko J.D., U. Lindahl: Molecular diversity of heparan sulfate. J Clin Invest 108, 169-173 (2001)
No DOI Found
19. Nakato H., K. Kimata: Heparan sulfate fine structure and specificity of proteoglycan functions. Biochim Biophys Acta 1573, 312-318 (2002)
No DOI Found
20. Mulloy B., M. Forster: Conformation and dynamics of heparin and heparan sulfate. Glycobiology 10, 1147-1156 (2000)
doi:10.1093/glycob/10.11.1147
21. Rudd T.R., S.E. Guimond, M.A. Skidmore, L. Duchesne, M. Guerrini, G. Torri, C. Cosentino, A. Brown, D.T. Clarke, J.E. Turnbull, D.G. Fernig, E.A. Yates: Influence of substitution pattern and cation binding on conformation and activity in heparin derivatives. Glycobiology 17, 983-993 (2007)
doi:10.1093/glycob/cwm062
22. Weinbaum S., J.M. Tarbell, E.R. Damiano: The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 9, 121-167 (2007)
doi:10.1146/annurev.bioeng.9.060906.151959
23. Reitsma S., D.W. Slaaf, H. Vink, M.A. van Zandvoort, M.G. oude Egbrink: The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 454, 345-359 (2007)
doi:10.1007/s00424-007-0212-8
24. Rehm M., D. Bruegger, F. Christ, P. Conzen, M. Thiel, M. Jacob, D. Chappell, M. Stoeckelhuber, U. Welsch, B. Reichart, K. Peter, B.F. Becker: Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation 116, 1896-1906 (2007)
doi:10.1161/CIRCULATIONAHA.106.684852
25. Mulivor A.W., H.H. Lipowsky: Inflammation- and ischemia-induced shedding of venular glycocalyx. Am J Physiol Heart Circ Physiol 286, H1672-H1680 (2004)
doi:10.1152/ajpheart.00832.2003
26. Ihrcke N.S., L.E. Wrenshall, B.J. Lindman, J.L. Platt: Role of heparan sulfate in immune system-blood vessel interactions. Immunol Today 14, 500-505 (1993)
doi:10.1016/0167-5699(93)90265-M
27. Ihrcke N.S., J.L. Platt: Shedding of heparan sulfate proteoglycan by stimulated endothelial cells: evidence for proteolysis of cell-surface molecules. J Cell Physiol 168, 625-637 (1996)
doi:10.1002/(SICI)1097-4652(199609)168:3<625::AID-JCP15>3.0.CO;2-Y
28. Constantinescu A.A., H. Vink, J.A. Spaan: Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface. Arterioscler Thromb Vasc Biol 23, 1541-1547 (2003)
doi:10.1161/01.ATV.0000085630.24353.3D
29. Noble M.I., A.J. Drake-Holland, H. Vink: Hypothesis: arterial glycocalyx dysfunction is the first step in the atherothrombotic process. QJM (2008)
doi:10.1093/qjmed/hcn024
30. Florian J.A., J.R. Kosky, K. Ainslie, Z. Pang, R.O. Dull, J.M. Tarbell: Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ Res 93, e136-e142 (2003)
doi:10.1161/01.RES.0000101744.47866.D5
31. Pahakis M.Y., J.R. Kosky, R.O. Dull, J.M. Tarbell: The role of endothelial glycocalyx components in mechanotransduction of fluid shear stress. Biochem Biophys Res Commun 355, 228-233 (2007)
doi:10.1016/j.bbrc.2007.01.137
32. Marshall L.J., L.S. Ramdin, T. Brooks, P.C. DPhil, J.K. Shute: Plasminogen activator inhibitor-1 supports IL-8-mediated neutrophil transendothelial migration by inhibition of the constitutive shedding of endothelial IL-8/heparan sulfate/syndecan-1 complexes. J Immunol 171, 2057-2065 (2003)
No DOI Found
33. Rosen S.D.: Ligands for L-selectin: homing, inflammation, and beyond. Annu Rev Immunol 22, 129-156 (2004)
doi:10.1146/annurev.immunol.21.090501.080131
34. Ley K.: The role of selectins in inflammation and disease. Trends Mol Med 9, 263-268 (2003)
doi:10.1016/S1471-4914(03)00071-6
35. Luo J., M. Kato, H. Wang, M. Bernfield, J. Bischoff: Heparan sulfate and chondroitin sulfate proteoglycans inhibit E-selectin binding to endothelial cells. J Cell Biochem 80, 522-531 (2001)
doi:10.1002/1097-4644(20010315)80:4<522::AID-JCB1006>3.0.CO;2-H
36. Koenig A., K.E. Norgard-Sumnicht, A. Varki: Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. J Clin Invest 101, 877-889 (1998)
doi:10.1172/JCI1509
37. Kawashima H., M. Hirose, J. Hirose, D. Nagakubo, A.H.K. Plaas, M. Miyasaka: Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin, and CD44. J Biol Chem 275, 35448-35456 (2000)
doi:10.1074/jbc.M003387200
38. Yanaka K., S.R. Spellman, J.B. McCarthy, T.R. Oegema, Jr., W.C. Low, P.J. Camarata: Reduction of brain injury using heparin to inhibit leukocyte accumulation in a rat model of transient focal cerebral ischemia. I. Protective mechanism. J Neurosurg 85, 1102-1107 (1996)
No DOI Found
39. Wang L., J.R. Brown, A. Varki, J.D. Esko: Heparin's anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins. J Clin Invest 110, 127-136 (2002)
No DOI Found
40. Wang J.G., J.G. Geng: Affinity and kinetics of P-selectin binding to heparin. Thromb Haemost 90, 309-316 (2003)
No DOI Found
41. Celie J.W., E.D. Keuning, R.H. Beelen, A.M. Drager, S. Zweegman, F.L. Kessler, R. Soininen, J. van den Born: Identification of L-selectin binding heparan sulfates attached to collagen type XVIII. J Biol Chem 280, 26965-26973 (2005)
doi:10.1074/jbc.M502188200
42. Norgard-Sumnicht K.E., N.M. Varki, A. Varki: Calcium-dependent heparin-like ligands for L-selectin in nonlyphoid endothelial cells. Science 261, 480-483 (1993)
doi:10.1126/science.7687382
43. Norgard-Sumnicht K. E., A. Varki: Endothelial heparan sulfate proteoglycans that bind to L-selectin have glucosamine residues with unsubstituted amino groups. J Biol Chem 270, 12012-12024 (1995)
doi:10.1074/jbc.270.20.12012
44. Giuffre L., A. Cordey, N. Monai, Y. Tardy, M. Schapira, O. Spertini: Monocyte adhesion to activated endothelium: role of L-selectin and heparan sulfate proteoglycans. J Cell Biology 136, 945-956 (1997)
doi:10.1083/jcb.136.4.945
45. Wang L., M. Fuster, P. Sriramarao, J.D. Esko: Endothelial heparan sulfate deficiency impairs L-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses. Nat Immunol 6, 902-910 (2005)
doi:10.1038/ni1233
46. Rops A.L., C.W. Jacobs, P.C. Linssen, J.B. Boezeman, J.F. Lensen, T.J. Wijnhoven, L.P. van den Heuvel, T.H. van Kuppevelt, J. van der Vlag, J.H. Berden: Heparan sulfate on activated glomerular endothelial cells and exogenous heparinoids influence the rolling and adhesion of leucocytes. Nephrol Dial Transplant 22, 1070-1077 (2007)
doi:10.1093/ndt/gfl801
47. Rops A.L., M.J. van den Hoven, M.M. Baselmans, J.F. Lensen, T.J. Wijnhoven, L.P. van den Heuvel, T.H. van Kuppevelt, J.H. Berden, J. van der Vlag: Heparan sulfate domains on cultured activated glomerular endothelial cells mediate leukocyte trafficking. Kidney Int 73, 52-62 (2008)
doi:10.1038/sj.ki.5002573
48. Netelenbos T., J. van den Born, F.L. Kessler, S. Zweegman, P.C. Huijgens, A.M. Drager: In vitro model for hematopoietic progenitor cell homing reveals endothelial heparan sulfate proteoglycans as direct adhesive ligands. J Leukoc Biol 74, 1035-1044 (2003)
doi:10.1189/jlb.1202593
49. Götte M.: Syndecans in inflammation. FASEB J 17, 575-591 (2003)
doi:10.1096/fj.02-0739rev
50. Alexopoulou A.N., H.A. Multhaupt, J.R. Couchman: Syndecans in wound healing, inflammation and vascular biology. Int J Biochem Cell Biol 39, 505-528 (2007)
doi:10.1016/j.biocel.2006.10.014
51. Patterson A.M., A. Cartwright, G. David, O. Fitzgerald, B. Bresnihan, B.A. Ashton, J.F. Middleton: Differential expression of syndecans and glypicans in chronically inflamed synovium. Ann Rheum Dis 67, 592-601 (2007)
doi:10.1136/ard.2006.063875
52. Johnson P., A. Maiti, K.L. Brown, R. Li: A role for the cell adhesion molecule CD44 and sulfation in leukocyte-endothelial cell adhesion during an inflammatory response? Biochem Pharmacol 59, 455-465 (2000)
doi:10.1016/S0006-2952(99)00266-X
53. Forster-Horvath C., L. Meszaros, E. Raso, B. Dome, A. Ladanyi, M. Morini, A. Albini, J. Timar: Expression of CD44v3 protein in human endothelial cells in vitro and in tumoral microvessels in vivo. Microvasc Res 68, 110-118 (2004)
doi:10.1016/j.mvr.2004.05.001
54. Shikata K., Y. Suzuki, J. Wada, K. Hirata, M. Matsuda, H. Kawashima, T. Suzuki, M. Iizuka, H. Makino, M. Miyasaka: L-selectin and its ligands mediate infiltration of mononuclear cells into kidney interstitium after ureteric obstruction. J Pathol 188, 93-99 (1999)
doi:10.1002/(SICI)1096-9896(199905)188:1<93::AID-PATH305>3.0.CO;2-#
55. Celie J.W., N. Rutjes, E.D. Keuning, R. Soininen, R. Heljasvaara, T. Pihlajaniemi, A.M. Dräger, S. Zweegman, F.L. Kessler, R.H. Beelen, S. Florquin, J. Aten, J. van den Born: Subendothelial heparan sulfate proteoglycans become major L-selectin and MCP-1 ligands upon renal ischemia/reperfusion. Am J Pathol 170, 1865-1878 (2007)
doi:10.2353/ajpath.2007.070061
56. Celie J.W., R.M. Reijmers, E.M. Slot, R.H. Beelen, M. Spaargaren, P.M. ter Wee, S. Florquin, J. van den Born: Tubulointerstitial heparan sulfate proteoglycan changes in human renal diseases correlate with leukocyte influx and proteinuria. Am J Physiol Renal Physiol 294, F253-F263 (2008)
doi:10.1152/ajprenal.00429.2007
57. Kawashima H., N. Watanabe, M. Hirose, X. Sun, K. Atarashi, T. Kimura, K. Shikata, M. Matsuda, D. Ogawa, R. Heljasvaara, M. Rehn, T. Pihlajaniemi, M. Miyasaka: Collagen XVIII, a basement membrane heparan sulfate proteoglycan, interacts with L-selectin and monocyte chemoattractant protein-1. J Biol Chem 278, 13069-13076 (2003)
doi:10.1074/jbc.M212244200
58. Li Y., H. Kawashima, N. Watanabe, M. Miyasaka: Identification and characterization of ligands for L-selectin in the kidney. II. Expression of chondroitin sulfate and heparan sulfate proteoglycans reactive with L-selectin. FEBS letters 444, 201-205 (1999)
doi:10.1016/S0014-5793(99)00046-0
59. Celie J.W., R.H. Beelen, J. van den Born: Effect of fixation protocols on in situ detection of L-selectin ligands. J Immunol Methods 298, 155-159 (2005)
doi:10.1016/j.jim.2005.01.009
60. Eriksson E.E.: No detectable endothelial- or leukocyte-derived L-selectin ligand activity on the endothelium in inflamed cremaster muscle venules. J Leukoc Biol (2008)
doi:10.1189/jlb.1107786
61. Hickey M.J., M. Forster, D. Mitchell, J. Kaur, C. De Caigny, P. Kubes: L-selectin facilitates emigration and extravascular locomotion of leukocytes during acute inflammatory responses in vivo. J Immunol 165, 7164-7170 (2000)
No DOI Found
62. Steeber D.A., P. Engel, A.S. Miller, M.P. Sheetz, T.F. Tedder: Ligation of L-selectin through conserved regions within the lectin domain activates signal transduction pathways and integrin function in human, mouse, and rat leukocytes. J Immunol159, 952-963 (1997)
No DOI Found
63. Chen C., X. Shang, T. Xu, L. Cui, J. Luo, X. Ba, S. Hao, X. Zeng: c-Abl is required for the signaling transduction induced by L-selectin ligation. Eur J Immunol 37, 3246-3258 (2007)
doi:10.1002/eji.200737221
64. Diamond M.S., R. Alon, C.A. Parkos, M.T. Quinn, T.A. Springer: Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD1). J Cell Biol 130, 1473-1482 (1995)
doi:10.1083/jcb.130.6.1473
65. Coombe D.R., S.M. Watt, C.R. Parish: Mac-1 (CD11b/CD18) and CD45 mediate the adhesion of hematopoietic progenitor cells to stromal cell elements via recognition of stromal heparan sulfate. Blood 84, 739-752 (1994)
No DOI Found
66. Watt S.M., J. Williamson, H. Genevier, J. Fawcett, D.L. Simmons, A. Hatzfeld, S.A. Nesbitt, D.R. Coombe: The heparin binding PECAM-1 adhesion molecule is expressed by CD34+ hematopoietic precursor cells with early myeloid and B-lymphoid cell phenotypes. Blood 82, 2649-2663 (1993)
No DOI Found
67. Coombe D.R., S.M. Stevenson, B.F. Kinnear, N.S. Gandhi, R.L. Mancera, R.I. Osmond, W.C. Kett: Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) and Its Interactions with Glycosaminoglycans: 2. Biochemical Analyses. Biochemistry 47, 4863-75 (2008)
doi:10.1021/bi7024595
68. Sotnikov I., R. Hershkoviz, V. Grabovsky, N. Ilan, L. Cahalon, I. Vlodavsky, R. Alon, O. Lider: Enzymatically quiescent heparanase augments T cell interactions with VCAM-1 and extracellular matrix components under versatile dynamic contexts. J Immunol 172, 5185-5193 (2004)
No DOI Found
69. Rot A., U.H. von Andrian: Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 22, 891-928 (2004)
doi:10.1146/annurev.immunol.22.012703.104543
70. Sadir R., A. Imberty, F. Baleux, H. Lortat-Jacob: Heparan sulfate/heparin oligosaccharides protect stromal cell-derived factor-1 (SDF-1)/CXCL12 against proteolysis induced by CD26/dipeptidyl peptidase IV. J Biol Chem 279, 43854-43860 (2004)
doi:10.1074/jbc.M405392200
71. Lortat-Jacob H., A. Grosdidier, A. Imberty: Structural diversity of heparan sulfate binding domains in chemokines. Proc Natl Acad Sci 99, 1229-1234 (2002)
doi:10.1073/pnas.032497699
72. Laguri C., F. Renzana-Seisdedos, H. Lortat-Jacob: Relationships between glycosaminoglycan and receptor binding sites in chemokines-the CXCL12 example. Carbohydr Res (2008) doi:10.1016/j.carres.2008.01.047
doi:10.1016/j.carres.2008.01.047
73. de Paz J.L., E.A. Moseman, C. Noti, L. Polito, U.H. von Andrian, P.H. Seeberger: Profiling heparin-chemokine interactions using synthetic tools. ACS Chem Biol 2, 735-744 (2007)
doi:10.1021/cb700159m
74. Handel T.M., Z. Johnson, S.E. Crown, E.K. Lau, A.E. Proudfoot: Regulation of protein function by glycosaminoglycans--as exemplified by chemokines. Annu Rev Biochem 74, 385-410 (2005)
doi:10.1146/annurev.biochem.72.121801.161747
75. Baltus T., K.S. Weber, Z. Johnson, A.E. Proudfoot, C. Weber: Oligomerization of RANTES is required for CCR1-mediated arrest but not CCR5-mediated transmigration of leukocytes on inflamed endothelium. Blood 102, 1985-1988 (2003)
doi:10.1182/blood-2003-04-1175
76. Ali S., S.J. Fritchley, B.T. Chaffey, J.A. Kirby: Contribution of the putative heparan sulfate-binding motif BBXB of RANTES to transendothelial migration. Glycobiology 12, 535-543 (2002)
doi:10.1093/glycob/cwf069
77. Proudfoot A.E., T.M. Handel, Z. Johnson, E.K. Lau, P. LiWang, I. Clark-Lewis, F. Borlat, T.N. Wells, M.H. Kosco-Vilbois: Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc Natl Acad Sci USA 100, 1885-1890 (2003)
doi:10.1073/pnas.0334864100
78. Hoogewerf A.J., G.S. Kuschert, A.E. Proudfoot, F. Borlat, I. Clark-Lewis, C.A. Power, T.N. Wells: Glycosaminoglycans mediate cell surface oligomerization of chemokines. Biochemistry 36, 13570-13578 (1997)
doi:10.1021/bi971125s
79. Tanaka Y., D.H. Adams, S. Shaw: Proteoglycans on endothelial cells present adhesion-inducing cytokines to leukocytes. Immunol Today 14, 111-115 (1993)
doi:10.1016/0167-5699(93)90209-4
80. Middleton J., A.M. Patterson, L. Gardner, C. Schmutz, B.A. Ashton: Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood 100, 3853-3860 (2002)
doi:10.1182/blood.V100.12.3853
81. Carter N.M., S. Ali, J.A. Kirby: Endothelial inflammation: the role of differential expression of N-deacetylase/N-sulphotransferase enzymes in alteration of the immunological properties of heparan sulphate. J Cell Sci116, 3591-3600 (2003)
doi:10.1242/jcs.00662
82. Hardy L.A., T.A. Booth, E.K. Lau, T.M. Handel, S. Ali, J.A. Kirby: Examination of MCP-1 (CCL2) partitioning and presentation during transendothelial leukocyte migration. Lab Invest 84, 81-90 (2004)
doi:10.1038/sj.labinvest.3700007
83. Middleton J., S. Neil, J. Wintle, I. Clark-Lewis, H. Moore, C. Lam, M. Auer, E. Hub, A. Rot: Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91, 385-395 (1997)
doi:10.1016/S0092-8674(00)80422-5
84. Halden Y., A. Rek, W. Atzenhofer, L. Szilak, A. Wabnig, A.J. Kungl: Interleukin-8 binds to syndecan-2 on human endothelial cells. Biochem J 377, 533-538 (2004)
doi:10.1042/BJ20030729
85. Patterson A.M., L. Gardner, J. Shaw, G. David, E. Loreau, L. Aguilar, B.A. Ashton, J. Middleton: Induction of a CXCL8 binding site on endothelial syndecan-3 in rheumatoid synovium. Arthritis Rheum 52, 2331-2342 (2005)
doi:10.1002/art.21222
86. Pelletier A.J., L.J. van der Laan, P. Hildbrand, M.A. Siani, D.A. Thompson, P.E. Dawson, B.E. Torbett, D.R. Salomon: Presentation of chemokine SDF-1 alpha by fibronectin mediates directed migration of T cells. Blood 96, 2682-2690 (2000)
No DOI Found
87. Salmi M., S. Jalkanen: Cell-surface enzymes in control of leukocyte trafficking. Nat Rev Immunol 5, 760-771 (2005)
doi:10.1038/nri1705
88. Nourshargh S., F.M. Marelli-Berg: Transmigration through venular walls: a key regulator of leukocyte phenotype and function. Trends Immunol 26, 157-165 (2005)
doi:10.1016/j.it.2005.01.006
89. Wang S., M.B. Voisin, K.Y. Larbi, J. Dangerfield, C. Scheiermann, M. Tran, P.H. Maxwell, L. Sorokin, S. Nourshargh: Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J Exp Med 203, 1519-1532 (2006)
doi:10.1084/jem.20051210
90. Segerer S., R. Djafarzadeh, H.J. Grone, C. Weingart, D. Kerjaschki, C. Weber, A.J. Kungl, H. Regele, A.E. Proudfoot, P.J. Nelson: Selective binding and presentation of CCL5 by discrete tissue microenvironments during renal inflammation. J Am Soc Nephrol 18, 1835-1844 (2007)
doi:10.1681/ASN.2006080837
91. Netelenbos T., S. Zuijderduijn, J. van den Born, F.L. Kessler, S. Zweegman, P.C. Huijgens, A.M. Drager: Proteoglycans guide SDF-1-induced migration of hematopoietic progenitor cells. J Leukoc Biol 72, 353-362 (2002)
No DOI Found
92. Vlodavsky I., A. Eldor, A. Haimovitz-Friedman, Y. Matzner, R. Ishai-Michaeli, O. Lider, Y. Naparstek, I.R. Cohen, I. R., Z. Fuks: Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. Invasion Metastasis 12, 112-127 (1992)
No DOI Found
93. Bartlett M.R., P.A. Underwood, C.R. Parish: Comparative analysis of the ability of leucocytes, endothelial cells and platelets to degrade the subendothelial basement membrane: evidence for cytokine dependence and detection of a novel sulfatase. Immunol Cell Biol 73, 113-124 (1995)
doi:10.1038/icb.1995.19
94. Mollinedo F., M. Nakajima, A. Llorens, E. Barbosa, S. Callejo, C. Gajate, A. Fabra: Major co-localization of the extracellular-matrix degradative enzymes heparanase and gelatinase in tertiary granules of human neutrophils. Biochem J 327 (Pt 3), 917-923 (1997)
No DOI Found
95. Sasaki N., N. Higashi, T. Taka, M. Nakajima, T. Irimura: Cell surface localization of heparanase on macrophages regulates degradation of extracellular matrix heparan sulfate. J Immunol 172, 3830-3835 (2004)
No DOI Found
96. Vreys V., G. David: Mammalian heparanase: what is the message? J Cell Mol Med 11, 427-452 (2007)
doi:10.1111/j.1582-4934.2007.00039.x
97. Benhamron S., H. Nechushtan, I. Verbovetski, A. Krispin, G. Bboud-Jarrous, E. Zcharia, E. Edovitsky, E. Nahari, T. Peretz, I. Vlodavsky, D. Mevorach: Translocation of active heparanase to cell surface regulates degradation of extracellular matrix heparan sulfate upon transmigration of mature monocyte-derived dendritic cells. J Immunol 176, 6417-6424 (2006)
No DOI Found
98. Vlodavsky I., N. Ilan, A. Naggi, B. Casu: Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr Pharm Des 13, 2057-2073 (2007)
doi:10.2174/138161207781039742
99. Ihrcke N.S., W. Parker, K.J. Reissner, J.L. Platt: Regulation of platelet heparanase during inflammation: role of pH and proteinases. J Cell Physiol 175, 255-267 (1998)
doi:10.1002/(SICI)1097-4652(199806)175:3<255::AID-JCP3>3.0.CO;2-N
100. Sanderson R.D., Y. Yang, T. Kelly, V. Macleod, Y. Dai, A. Theus: Enzymatic remodeling of heparan sulfate proteoglycans within the tumor microenvironment: Growth regulation and the prospect of new cancer therapies. J Cell Biochem 96, 897-905 (2005)
doi:10.1002/jcb.20602
101. Hershkoviz R., F. Mor, H.Q. Miao, I. Vlodavsky, O. Lider: Differential effects of polysulfated polysaccharide on experimental encephalomyelitis, proliferation of autoimmune T cells, and inhibition of heparanase activity. J Autoimmun 8, 741-750 (1995)
doi:10.1006/jaut.1995.0055
102. Edovitsky E., I. Lerner, E. Zcharia, T. Peretz, I. Vlodavsky, M. Elkin: Role of endothelial heparanase in delayed-type hypersensitivity. Blood 107, 3609-3616 (2006)
doi:10.1182/blood-2005-08-3301
103. Moseley R., R.J. Waddington, G. Embery: Degradation of glycosaminoglycans by reactive oxygen species derived from stimulated polymorphonuclear leukocytes. Biochim Biophys Acta 1362, 221-231 (1997)
No DOI Found
104. Moseley R., R. Waddington, P. Evans, B. Halliwell, G. Embery: The chemical modification of glycosaminoglycan structure by oxygen-derived species in vitro. Biochim Biophys Acta 1244, 245-252 (1995)
No DOI Found
105. Raats C.J., M.A. Bakker, J. van den Born, J.H. Berden: Hydroxyl radicals depolymerize glomerular heparan sulfate in vitro and in experimental nephrotic syndrome. J Biol Chem 272, 26734-26741 (1997)
doi:10.1074/jbc.272.42.26734
106. Vaday G.G., O. Lider: Extracellular matrix moieties, cytokines, and enzymes: dynamic effects on immune cell behavior and inflammation. J Leukoc Biol 67, 149-159 (2000)
No DOI Found
107. Johnson G.B., G.J. Brunn, Y. Kodaira, J.L. Platt: Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J Immunol 168, 5233-5239 (2002)
No DOI Found
108. Hecht I., R. Hershkoviz, S. Shivtiel, T. Lapidot, I.R. Cohen, O. Lider, L. Cahalon: Heparin-disaccharide affects T cells: inhibition of NF-kappaB activation, cell migration, and modulation of intracellular signaling. J Leukoc Biol 75, 1139-1146 (2004)
doi:10.1189/jlb.1203659
109. Hershkoviz R., H. Schor, A. Ariel, I. Hecht, I.R. Cohen, O. Lider, L. Cahalon: Disaccharides generated from heparan sulphate or heparin modulate chemokine-induced T-cell adhesion to extracellular matrix. Immunology 99, 87-93 (2000)
doi:10.1046/j.1365-2567.2000.00931.x
110. Cahalon L., O. Lider, H. Schor, A. Avron, D. Gilat, R. Hershkoviz, R. Margalit, A. Eshel, O. Shoseyev, I.R. Cohen: Heparin disaccharides inhibit tumor necrosis factor-alpha production by macrophages and arrest immune inflammation in rodents. Int Immunol 9, 1517-1522 (1997)
doi:10.1093/intimm/9.10.1517
111. Lider O., L. Cahalon, D. Gilat, R. Hershkoviz, D. Siegel, R. Margalit, O. Shoseyov, I.R. Cohen: A disaccharide that inhibits tumor necrosis factor alpha is formed from the extracellular matrix by the enzyme heparanase. Proc Natl Acad Sci USA 92, 5037-5041 (1995)
doi:10.1073/pnas.92.11.5037
112. Li J., L.F. Brown, R.J. Laham, R. Volk, M. Simons: Macrophage-dependent regulation of syndecan gene expression. Circ Res 81, 785-796 (1997)
No DOI Found
113. Manakil J.F., P.B. Sugerman, H. Li, G.J. Seymour, P.M. Bartold: Cell-surface proteoglycan expression by lymphocytes from peripheral blood and gingiva in health and periodontal disease. J Dent Res 80, 1704-1710 (2001)
No DOI Found
114. Campbell E.J., C.A. Owen: The sulfate groups of chondroitin sulfate- and heparan sulfate-containing proteoglycans in neutrophil plasma membranes are novel binding sites for human leukocyte elastase and cathepsin G. J Biol Chem 282, 14645-14654 (2007)
doi:10.1074/jbc.M608346200
115. Kaneider N.C., P. Egger, S. Dunzendorfer, C.J. Wiedermann: Syndecan-4 as antithrombin receptor of human neutrophils. Biochem Biophys Res Commun 287, 42-46 (2001)
doi:10.1006/bbrc.2001.5534
116. Kaneider N.C., C.M. Reinisch, S. Dunzendorfer, J. Romisch, C.J. Wiedermann: Syndecan-4 mediates antithrombin-induced chemotaxis of human peripheral blood lymphocytes and monocytes. J Cell Sci 115, 227-236 (2002)
No DOI Found
117. Pakula R., A. Melchior, A. Denys, C. Vanpouille, J. Mazurier, F. Allain: Syndecan-1/CD147 association is essential for cyclophilin B-induced activation of p44/42 mitogen-activated protein kinases and promotion of cell adhesion and chemotaxis. Glycobiology 17, 492-503 (2007)
doi:10.1093/glycob/cwm009
118. Ali S., A.C. Palmer, B. Banerjee, S.J. Fritchley, J.A. Kirby: Examination of the function of RANTES, MIP-1alpha, and MIP-1beta following interaction with heparin-like glycosaminoglycans. J Biol Chem 275, 11721-11727 (2000)
doi:10.1074/jbc.275.16.11721
119. Wang D., J. Sai, A. Richmond: Cell surface heparan sulfate participates in CXCL1-induced signaling. Biochemistry 42, 1071-1077 (2003)
doi:10.1021/bi026425a
120. Roscic-Mrkic B., M. Fischer, C. Leemann, A. Manrique, C.J. Gordon, J.P. Moore, A.E. Proudfoot, A. Trkola: RANTES (CCL5) uses the proteoglycan CD44 as an auxiliary receptor to mediate cellular activation signals and HIV-1 enhancement. Blood 102, 1169-1177 (2003)
doi:10.1182/blood-2003-02-0488
121. Chang T.L., C.J. Gordon, B. Roscic-Mrkic, C. Power, A.E. Proudfoot, J.P. Moore, A. Trkola: Interaction of the CC-chemokine RANTES with glycosaminoglycans activates a p44/p42 mitogen-activated protein kinase-dependent signaling pathway and enhances human immunodeficiency virus type 1 infectivity. J Virol 76, 2245-2254 (2002)
doi:10.1128/jvi.76.5.2245-2254.2002
122. Allain F., C. Vanpouille, M. Carpentier, M.C. Slomianny, S. Durieux, G. Spik: Interaction with glycosaminoglycans is required for cyclophilin B to trigger integrin-mediated adhesion of peripheral blood T lymphocytes to extracellular matrix. Proc Natl Acad Sci USA 99, 2714-2719 (2002)
doi:10.1073/pnas.052284899
123. Vanpouille C., A. Deligny, M. Delehedde, A. Denys, A. Melchior, X. Lienard, M. Lyon, J. Mazurier, Fernig, D. G., and Allain, F.:The heparin/heparan sulfate sequence that interacts with cyclophilin B contains a 3-O-sulfated N-unsubstituted glucosamine residue. J Biol Chem 282, 24416-24429 (2007)
doi:10.1074/jbc.M701835200
124. Floris S., J. van den Born, S.M. van der Pol, C.D. Dijkstra, H.E. de Vries: Heparan sulfate proteoglycans modulate monocyte migration across cerebral endothelium. J Neuropathol Exp Neurol 62, 780-790 (2003)
No DOI Found
125. Götte M., A.M. Joussen, C. Klein, P. Andre, D.D. Wagner, M.T. Hinkes, B. Kirchhof, A.P. Adamis, M. Bernfield: Role of syndecan-1 in leukocyte-endothelial interactions in the ocular vasculature. Invest Ophthalmol Vis Sci 43, 1135-1141 (2002)
No DOI Found
126. Gotte M., M. Bernfield, A.M. Joussen: Increased leukocyte-endothelial interactions in syndecan-1-deficient mice involve heparan sulfate-dependent and -independent steps. Curr Eye Res 30, 417-422 (2005)
doi:10.1080/02713680590956289
127. Rops A.L., M. Gotte, M.H. Baselmans, M.J. van den Hoven, E.J. Steenbergen, J.F. Lensen, T.J. Wijnhoven, F. Cevikbas, L.P. van den Heuvel, T.H. van Kuppevelt, J.H. Berden, J. and van der Vlag: Syndecan-1 deficiency aggravates anti-glomerular basement membrane nephritis. Kidney Int 72, 1204-1215 (2007)
doi:10.1038/sj.ki.5002514
128. Vanhoutte D., M.W. Schellings, M. Gotte, M. Swinnen, V. Herias, M.K. Wild, D. Vestweber, E. Chorianopoulos, V. Cortes, A. Rigotti, M.A. Stepp, F. van de Werf, P. Carmeliet, Y.M. Pinto, S. Heymans: Increased expression of syndecan-1 protects against cardiac dilatation and dysfunction after myocardial infarction. Circulation 115, 475-482 (2007)
doi:10.1161/CIRCULATIONAHA.106.644609
129. Garner O.B., Y. Yamaguchi, J.D. Esko, V. Videm: Small changes in lymphocyte development and activation in mice through tissue-specific alteration of heparan sulphate. Immunology (2008)
No DOI found
130. Morgan M.R., M.J. Humphries, M.D. Bass: Synergistic control of cell adhesion by integrins and syndecans. Nat Rev Mol Cell Biol 8, 957-969 (2007)
doi:10.1038/nrm2289
131. Parish C.R.: The role of heparan sulphate in inflammation. Nat Rev Immunol 6, 633-643 (2006)
doi:10.1038/nri1918
132. Zhang Y., M. Pasparakis, G. Kollias, M. Simons: Myocyte-dependent regulation of endothelial cell syndecan-4 expression. Role of TNF-alpha. J Biol Chem 274, 14786-14790 (1999)
doi:10.1074/jbc.274.21.14786
133. Elenius K., S. Vainio, M. Laato, M. Salmivirta, I. Thesleff, M. Jalkanen: Induced expression of syndecan in healing wounds. J Cell Biol 114, 585-595 (1991)
doi:10.1083/jcb.114.3.585
134. Gallo R., C. Kim, R. Kokenyesi, N.S. Adzick, M. Bernfield: Syndecans-1 and -4 are induced during wound repair of neonatal but not fetal skin. J Invest Dermatol 107, 676-683 (1996)
doi:10.1111/1523-1747.ep12365571
135. Watanabe A., T. Mabuchi, E. Satoh, K. Furuya, L. Zhang, S. Maeda, H. Naganuma: Expression of syndecans, a heparan sulfate proteoglycan, in malignant gliomas: participation of nuclear factor-kappaB in upregulation of syndecan-1 expression. J Neurooncol 1-8 (2005)
No DOI Found
136. Jaakkola P., T. Vihinen, M. Jalkanen: Proximal promoter-independent activation of the far-upstream FGF-inducible response element of syndecan-1 gene. Biochem Biophys Res Commun 278, 432-439 (2000)
doi:10.1006/bbrc.2000.3812
137. Jaakkola P., M. Jalkanen: Transcriptional regulation of Syndecan-1 expression by growth factors. Prog Nucleic Acid Res Mol Biol 63, 109-138 (1999)
doi:10.1016/S0079-6603(08)60721-7
138. Jaakkola P., A. Maatta, M. Jalkanen: The activation and composition of FiRE (an FGF-inducible response element) differ in a cell type- and growth factor-specific manner. Oncogene 17, 1279-1286 (1998)
doi:10.1038/sj.onc.1202002
139. Dalmay T., D.R. Edwards: MicroRNAs and the hallmarks of cancer. Oncogene 25, 6170-6175 (2006)
doi:10.1038/sj.onc.1209911
140. Filipowicz W., S.N. Bhattacharyya, N. Sonenberg: Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9, 102-114 (2008)
doi:10.1038/nrg2290
141. Fitzgerald M.L., Z. Wang, P.W. Park, G. Murphy, M. Bernfield: Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase. J Cell Biol 148, 811-824 (2000)
doi:10.1083/jcb.148.4.811
142. Li Q., P.W. Park, C.L. Wilson, W.C. Parks: Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111, 635-646 (2002)
doi:10.1016/S0092-8674(02)01079-6
143. Mahtouk K., D. Hose, P. Raynaud, M. Hundemer, M. Jourdan, E. Jourdan, V. Pantesco, M. Baudard, J. de Vos, M. Larroque, T. Moehler, J.F. Rossi, T. Reme, H. Goldschmidt, B. Klein: Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma. Blood 109, 4914-4923 (2007)
doi:10.1182/blood-2006-08-043232
144. Yang Y., V. Macleod, H.Q. Miao, A. Theus, F. Zhan, J.D. Shaughnessy, Jr., J. Sawyer, J.P. Li, E. Zcharia, I. Vlodavsky, R.D. Sanderson: Heparanase enhances syndecan-1 shedding: a novel mechanism for stimulation of tumor growth and metastasis. J Biol Chem 282, 13326-13333 (2007)
doi:10.1074/jbc.M611259200
145. Santiago B., F. Baleux, G. Palao, I. Gutierrez-Canas, J.C. Ramirez, F. Renzana-Seisdedos, J.L. Pablos: CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans. Arthritis Res Ther 8, R43 (2006)
doi:10.1186/ar1900
146. Uchimura K., M. Morimoto-Tomita, A. Bistrup, J. Li, M. Lyon, J. Gallagher, Z. Werb, S.D. Rosen: HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1. BMC Biochem 7, 2 (2006)
doi:10.1186/1471-2091-7-2
147. Huopaniemi L., M. Kolmer, J. Niittymaki, M. Pelto-Huikko, R. Renkonen: Inflammation-induced transcriptional regulation of Golgi transporters required for the synthesis of sulfo sLex glycan epitopes. Glycobiology 14, 1285-1294 (2004)
doi:10.1093/glycob/cwh131
148. Netelenbos T., J. van den Born, F.L. Kessler, S. Zweegman, P.A. Merle, J.W. van Oostveen, J. Zwaginga, P.C. Huijgens, A.M. Drager: Proteoglycans on bone marrow endothelial cells bind and present SDF-1 towards hematopoietic progenitor cells. Leukemia 17, 175-184 (2003)
doi:10.1038/sj.leu.2402738
149. Netelenbos T., A.M. Dräger, B. van het Hof, F.L. Kessler, C. Delouis, P.C. Huijgens, J. van den Born, W. van Dijk: Differences in sulfation patterns of heparan sulfate derived from human bone marrow and umbilical vein endothelial cells. Exp Hematol 29, 884-893 (2001)
doi:10.1016/S0301-472X(01)00653-1
150. Powell A.K., E.A. Yates, D.G. Fernig, J.E. Turnbull: Interactions of heparin/heparan sulfate with proteins: appraisal of structural factors and experimental approaches. Glycobiology 14, 17R-30R (2004)
doi:10.1093/glycob/cwh051
151. Coombe D.R., W.C. Kett: Heparan sulfate-protein interactions: therapeutic potential through structure-function insights. Cell Mol Life Sci 62, 410-424 (2005)
doi:10.1007/s00018-004-4293-7
152. Vlodavsky I., Y. Friedmann: Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J Clin Invest 108, 341-347 (2001)
No DOI Found
153. Fuster M.M., J.D. Esko: The sweet and sour of cancer: glycans as novel therapeutic targets. Nat Rev Cancer 5, 526-542 (2005)
doi:10.1038/nrc1649
154. Ferro V., K. Dredge, L. Liu, E. Hammond, I. Bytheway, C. Li, K. Johnstone, T. Karoli, K. Davis, E. Copeman, A. Gautam: PI-88 and novel heparan sulfate mimetics inhibit angiogenesis. Semin Thromb Hemost 33, 557-568 (2007)
doi:10.1055/s-2007-982088
155. Nelson R.M., O. Cecconi, W.G. Roberts, A. Aruffo, R.J. Linhardt, M.P. Bevilacqua: Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood 82, 3253-3258 (1993)
No DOI Found
156. Borsig L., R. Wong, R.O. Hynes, N.M. Varki, A. Varki: Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci 99, 2193-2198 (2001)
doi:10.1073/pnas.261704098
157. Borsig L., R. Wong, J. Feramisco, D.R. Nadeau, N.M. Varki, A. Varki: Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci 98, 3352-3357 (2001)
doi:10.1073/pnas.061615598
158. Robertson J.H., A.M. Iga, K.M. Sales, M.C. Winslet, A.M. Seifalian: Integrins: a method of early intervention in the treatment of colorectal liver metastases. Curr Pharm Des 14, 296-305 (2008)
doi:10.2174/138161208783413284
159. Lindahl U.: Heparan sulfate-protein interactions--a concept for drug design? Thromb Haemost 98, 109-115 (2007)
160. de Paz J.L., C. Noti, P.H. Seeberger: Microarrays of synthetic heparin oligosaccharides. J Am Chem Soc 128, 2766-2767 (2006)
doi:10.1021/ja057584v
PMid:16506732
161. Noti C., J.L. de Paz, L. Polito, P.H. Seeberger: Preparation and use of microarrays containing synthetic heparin oligosaccharides for the rapid analysis of heparin-protein interactions. Chemistry 12, 8664-8686 (2006)
No DOI Found
162. Kalicki R.M., F. Aregger, L. Alberio, B. Lammle, F.J. Frey, D.E. Uehlinger: Use of the pentasaccharide fondaparinux as an anticoagulant during haemodialysis. Thromb Haemost 98, 1200-1207 (2007)
No DOI Found
163. Walenga J.M., W.P. Jeske, M.M. Samama, F.X. Frapaise, R.L. Bick, J. Fareed: Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent. Expert Opin Investig Drugs 11, 397-407 (2002)
doi:10.1517/13543784.11.3.397
164. Johnson Z., A.E. Proudfoot, T.M. Handel: Interaction of chemokines and glycosaminoglycans: a new twist in the regulation of chemokine function with opportunities for therapeutic intervention. Cytokine Growth Factor Rev 16, 625-636 (2005)
doi:10.1016/j.cytogfr.2005.04.006
165. Rot A.:In situ binding assay for studying chemokine interactions with endothelial cells. J Immunol Methods 273, 63-71 (2003)
doi:10.1016/S0022-1759(02)00502-1
166. Wu J.Y., L. Feng, H.T. Park, N. Havlioglu, L. Wen, H. Tang, K.B. Bacon, Zh. Jiang, Xc. Zhang, Y. Rao: The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 410, 948-952 (2001)
doi:10.1038/35073616
167. Prasad A., Z. Qamri, J. Wu, R.K. Ganju: Slit-2/Robo-1 modulates the CXCL12/CXCR4-induced chemotaxis of T cells. J Leukoc Biol 82, 465-476 (2007)
doi:10.1189/jlb.1106678
168. Zhang F., F. Ronca, R.J. Linhardt, R.U. Margolis: Structural determinants of heparan sulfate interactions with Slit proteins. Biochem Biophys Res Commun 317, 352-357 (2004)
doi:10.1016/j.bbrc.2004.03.059
169. Shipp E.L., L.C. Hsieh-Wilson: Profiling the sulfation specificities of glycosaminoglycan interactions with growth factors and chemotactic proteins using microarrays. Chem Biol 14, 195-208 (2007)
doi:10.1016/j.chembiol.2006.12.009
170. Kanellis J., G.E. Garcia, P. Li, G. Parra, C.B. Wilson, Y. Rao, S. Han, C.W. Smith, R.J. Johnson, J.Y. Wu, L. Feng: Modulation of inflammation by slit protein in vivo in experimental crescentic glomerulonephritis. Am J Pathol 165, 341-352 (2004)
No DOI Found
171. Altay T., B. McLaughlin, J.Y. Wu, T.S. Park, J.M. Gidday: Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia. Exp Neurol 207, 186-194 (2007)
doi:10.1016/j.expneurol.2007.06.028
172. Wan J.G., J.S. Mu, H.S. Zhu, J.G. Geng: N-desulfated non-anticoagulant heparin inhibits leukocyte adhesion and transmigration in vitro and attenuates acute peritonitis and ischemia and reperfusion injury in vivo. Inflamm Res 51, 435-443 (2002)
doi:10.1007/PL00000290
173. Weber J.R., K. Angstwurm, T. Rosenkranz, U. Lindauer, D. Freyer, W. Burger, C. Busch, K.M. Einhaupl, U. Dirnagl: Heparin inhibits leukocyte rolling in pial vessels and attenuates inflammatory changes in a rat model of experimental bacterial meningitis. J Cereb Blood Flow Metab 17, 1221-1229 (1997)
doi:10.1097/00004647-199711000-00011
174. Willenborg D.O., C.R. Parish: Inhibition of allergic encephalomyelitis in rats by treatment with sulfated polysaccharides. J Immunol 140, 3401-3405 (1988)
No DOI Found
175. Vancheri C., C. Mastruzzo, F. Armato, V. Tomaselli, S. Magri, M.P. Pistorio, M. LaMicela, L. D'Amico, N. Crimi: Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol 108, 703-708 (2001)
doi:10.1067/mai.2001.118785
176. Seeds E.A., C.P. Page: Heparin inhibits allergen-induced eosinophil infiltration into guinea-pig lung via a mechanism unrelated to its anticoagulant activity. Pulm Pharmacol Ther 14, 111-119 (2001)
doi:10.1006/pupt.2000.0277
177. Wang Q.L., X.Y. Shang, S.L. Zhang, J.B. Ji, Y.N. Cheng, Y.J. Meng, Y.J. Zhu: Effects of inhaled low molecular weight heparin on airway allergic inflammation in aerosol-ovalbumin-sensitized guinea pigs. Jpn J Pharmacol 82, 326-330 (2000)
doi:10.1254/jjp.82.326
178. Bowler S.D., S.M. Smith, P.S. Lavercombe: Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects. Am Rev Respir Dis 147, 160-163 (1993)
No DOI Found
179. Darien B.J., J. Fareed, K.S. Centgraf, A.P. Hart, P.S. MacWilliams, M.K. Clayton, H. Wolf, K.T. Kruse-Elliott: Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model. Shock 9, 274-281 (1998)
doi:10.1097/00024382-199804000-00007
180. Harada N., K. Okajima, M. Uchiba: Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion-induced liver injury in rats. Crit Care Med 34, 1883-1891 (2006)
doi:10.1097/01.CCM.0000220764.10155.03
181. Baram D., M. Rashkovsky, R. Hershkoviz, I. Drucker, T. Reshef, S. Ben-Shitrit, Y.A. Mekori: Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation. Clin Exp Immunol 110, 485-491 (1997)
doi:10.1046/j.1365-2249.1997.4541471.x
182. Frizelle S., J. Schwarz, S.A. Huber, K. Leslie: Evaluation of the effects of low molecular weight heparin on inflammation and collagen deposition in chronic coxsackievirus B3-induced myocarditis in A/J mice. Am J Pathol 141, 203-209 (1992)
No DOI Found
183. Gottmann U., A. Mueller-Falcke, P. Schnuelle, R. Birck, V. Nickeleit, F.J. van der Woude, B.A. Yard, C. Braun: Influence of hypersulfated and low molecular weight heparins on ischemia/reperfusion: injury and allograft rejection in rat kidneys. Transpl Int 20, 542-549 (2007)
doi:10.1111/j.1432-2277.2007.00471.x
184. Shin C.S., J.U. Han, J.L. Kim, P.J. Schenarts, L.D. Traber, H. Hawkins, D.L. Traber: Heparin attenuated neutrophil infiltration but did not affect renal injury induced by ischemia reperfusion. Yonsei Med J 38, 133-141 (1997)
No DOI Found
185. Braun C., M. Schultz, L. Fang, M. Schaub, W.E. Back, D. Herr, V. Laux, P. Rohmeiss, P. Schnuelle, F.J. van der Woude: Treatment of chronic renal allograft rejection in rats with a low-molecular-weight heparin (reviparin). Transplantation 72, 209-215 (2001)
doi:10.1097/00007890-200107270-00007
186. Frank R.D., G. Schabbauer, T. Holscher, Y. Sato, M. Tencati, R. Pawlinski, N. Mackman: The synthetic pentasaccharide fondaparinux reduces coagulation, inflammation and neutrophil accumulation in kidney ischemia-reperfusion injury. J Thromb Haemost 3, 531-540 (2005)
doi:10.1111/j.1538-7836.2005.01188.x
187. Frank R.D., T. Holscher, G. Schabbauer, M. Tencati, R. Pawlinski, J.I. Weitz, N. Mackman: A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury. Thromb Haemost 96, 802-806 (2006)
No DOI Found
188. Johnson Z., M.H. Kosco-Vilbois, S. Herren, R. Cirillo, V. Muzio, P. Zaratin, M. Carbonatto, M. Mack, A. Smailbegovic, M. Rose, R. Lever, C. Page, T.N. Wells, A.E. Proudfoot: Interference with heparin binding and oligomerization creates a novel anti-inflammatory strategy targeting the chemokine system. J Immunol173, 5776-5785 (2004)
No DOI Found
Abbreviations: HSPGs: heparan sulfate proteoglycans; GAGs: glycosaminoglycans; HS: heparan sulfate; CS: chondroitin sulfate; DS: dermatan sulfate; KS: keratan sulfate; ECM: extracellular matrix; NDST-1: N-deacetylase N-sulfotransferase-1; MMPs: matrix metalloproteinases; TLRs: Toll-like receptors
Key Words: Heparan Sulfate Proteoglycans, Adhesion Molecules, Chemokines, Inflammation, Review
Send correspondence to: Johanna W.A.M. Celie, Dept. Molecular Cell Biology and Immunology, VU University Medical Center, P.O.Box 7057, 1007 MB Amsterdam, the Netherlands, Tel: 31 20 444 8079, Fax: 31 20 444 8081, E-mail:p.celie@vumc.nl