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  • Review Article
  • Published:

The role of heparan sulphate in inflammation

Nature Reviews Immunology volume 6, pages 633–643 (2006)Cite this article

Key Points

  • Leukocyte extravasation into inflammatory sites is a multistep process involving cell adhesion, transendothelial migration and entry into tissues.

  • Heparan sulphate proteoglycans (HSPGs) are distributed throughout the blood-vessel wall and are now known to participate in every stage of leukocyte extravasation.

  • The multifunctional role of HSPGs in inflammation is mainly due to their heparan sulphate chains, which are negatively charged polysaccharides with enormous sequence diversity. This allows HSPGs to interact with a vast array of ligands.

  • Owing to their structural diversity, heparan sulphates can do the following: function as lymphocyte (L)-selectin ligands and mediate initial adhesion of leukocytes to the inflamed endothelium; bind chemokines and establish chemokine gradients within the vessel wall; transport chemokines across the vessel wall through a process known as transcytosis; and provide a reservoir of growth factors and cytokines within the subendothelial basement membrane, which are released by the heparan-sulphate-degrading enzyme heparanase during inflammatory responses.

  • HSPGs in the subendothelial basement membrane can also act as a barrier to leukocyte extravasation, with heparanase having an important role in degrading this barrier.

  • Heparan-sulphate mimetics that block some of these HSPG-dependent processes have considerable potential as anti-inflammatory drugs.

Abstract

The polysaccharide heparan sulphate is ubiquitously expressed as a proteoglycan in extracellular matrices and on cell surfaces. Heparan sulphate has marked sequence diversity that allows it to specifically interact with many proteins. This Review focuses on the multiple roles of heparan sulphate in inflammatory responses and, in particular, on its participation in almost every stage of leukocyte transmigration through the blood-vessel wall. Heparan sulphate is involved in the initial adhesion of leukocytes to the inflamed endothelium, the subsequent chemokine-mediated transmigration through the vessel wall and the establishment of both acute and chronic inflammatory reactions.

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Figure 1: The importance of heparan sulphate at different stages during the entry of leukocytes into sites of inflammation.
Figure 2: The structure of heparan sulphate and its location in the blood-vessel wall.
Figure 3: The multiple roles of the endoglycosidase heparanase in leukocyte migration through the vessel wall.

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References

  1. Muller, W. A. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 24, 327–334 (2003).

    CAS  PubMed  Google Scholar 

  2. Yadav, R., Larbi, K. Y., Young, R. E. & Nourshargh, S. Migration of leukocytes through the vessel wall and beyond. Thromb. Haemost. 90, 598–606 (2003).

    CAS  PubMed  Google Scholar 

  3. Lowe, J. B. Glycan-dependent leukocyte adhesion and recruitment in inflammation. Curr. Opin. Cell Biol. 15, 531–538 (2003).

    CAS  PubMed  Google Scholar 

  4. Rot, A. & von Andrian, U. H. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu. Rev. Immunol. 22, 891–928 (2004).

    CAS  PubMed  Google Scholar 

  5. Nourshargh, S. & Marelli-Berg, F. M. Transmigration through venular walls: a key regulator of leukocyte phenotype and function. Trends Immunol. 26, 157–165 (2005).

    CAS  PubMed  Google Scholar 

  6. Parish, C. R. et al. Treatment of central nervous system inflammation with inhibitors of basement membrane degradation. Immunol. Cell Biol. 76, 104–113 (1998).

    CAS  PubMed  Google Scholar 

  7. Dejana, E., Spagnuolo, R. & Bazzoni, G. Interendothelial junctions and their role in the control of angiogenesis, vascular permeability and leukocyte transmigration. Thromb. Haemost. 86, 308–315 (2001).

    CAS  PubMed  Google Scholar 

  8. Taylor, K. R. & Gallo, R. L. Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. FASEB J. 20, 9–22 (2006).

    CAS  PubMed  Google Scholar 

  9. Esko, J. D. & Selleck, S. B. Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu. Rev. Biochem. 71, 435–471 (2002).

    CAS  PubMed  Google Scholar 

  10. Gallagher, J. T. Heparan sulfate: growth control with a restricted sequence menu. J. Clin. Invest. 108, 357–361 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Turnbull, J., Powell, A. & Guimond, S. Heparan sulfate: decoding a dynamic multifunctional cell regulator. Trends Cell Biol. 11, 75–82 (2001).

    CAS  PubMed  Google Scholar 

  12. Gotte, M. Syndecans in inflammation. FASEB J. 17, 575–591 (2003).

    CAS  PubMed  Google Scholar 

  13. Johnson, Z., Proudfoot, A. E. & Handel, T. M. 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).

    CAS  PubMed  Google Scholar 

  14. Rops, A. L. et al. Heparan sulfate proteoglycans in glomerular inflammation. Kidney Int. 65, 768–785 (2004).

    CAS  PubMed  Google Scholar 

  15. Kim, C. W., Goldberger, O. A., Gallo, R. L. & Bernfield, M. Members of the syndecan family of heparan sulfate proteoglycans are expressed in distinct cell-, tissue-, and development-specific patterns. Mol. Biol. Cell 5, 797–805 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Gengrinovitch, S. et al. Glypican-1 is a VEGF165 binding proteoglycan that acts as an extracellular chaperone for VEGF165. J. Biol. Chem. 274, 10816–10822 (1999).

    CAS  PubMed  Google Scholar 

  17. Schmidt, A., Echtermeyer, F., Alozie, A., Brands, K. & Buddecke, E. Plasmin- and thrombin-accelerated shedding of syndecan-4 ectodomain generates cleavage sites at Lys(114)–Arg(115) and Lys(129)–Val(130) bonds. J. Biol. Chem. 280, 34441–34446 (2005).

    CAS  PubMed  Google Scholar 

  18. Clasper, S. et al. Inducible expression of the cell surface heparan sulfate proteoglycan syndecan-2 (fibroglycan) on human activated macrophages can regulate fibroblast growth factor action. J. Biol. Chem. 274, 24113–24123 (1999).

    CAS  PubMed  Google Scholar 

  19. Kaneider, N. C., Egger, P., Dunzendorfer, S. & Wiedermann, C. J. Syndecan-4 as antithrombin receptor of human neutrophils. Biochem. Biophys. Res. Commun. 287, 42–46 (2001).

    CAS  PubMed  Google Scholar 

  20. Kaneider, N. C., Reinisch, C. M., Dunzendorfer, S., Romisch, J. & Wiedermann, C. J. Syndecan-4 mediates antithrombin-induced chemotaxis of human peripheral blood lymphocytes and monocytes. J. Cell Sci. 115, 227–236 (2002).

    CAS  PubMed  Google Scholar 

  21. Saphire, A. C., Bobardt, M. D., Zhang, Z., David, G. & Gallay, P. A. Syndecans serve as attachment receptors for human immunodeficiency virus type 1 on macrophages. J. Virol. 75, 9187–9200 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Jones, K. S., Petrow-Sadowski, C., Bertolette, D. C., Huang, Y. & Ruscetti, F. W. Heparan sulfate proteoglycans mediate attachment and entry of human T-cell leukemia virus type 1 virions into CD4+ T cells. J. Virol. 79, 12692–12702 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sanderson, R. D. & Borset, M. Syndecan-1 in B lymphoid malignancies. Ann. Hematol. 81, 125–135 (2002).

    CAS  PubMed  Google Scholar 

  24. Wong, S. H., Hamel, L., Chevalier, S. & Philip, A. Endoglin expression on human microvascular endothelial cells association with betaglycan and formation of higher order complexes with TGF-β signalling receptors. Eur. J. Biochem. 267, 5550–5560 (2000).

    CAS  PubMed  Google Scholar 

  25. Bennett, K. L. et al. CD44 isoforms containing exon V3 are responsible for the presentation of heparin-binding growth factor. J. Cell Biol. 128, 687–698 (1995).

    CAS  PubMed  Google Scholar 

  26. Jones, M., Tussey, L., Athanasou, N. & Jackson, D. G. Heparan sulfate proteoglycan isoforms of the CD44 hyaluronan receptor induced in human inflammatory macrophages can function as paracrine regulators of fibroblast growth factor action. J. Biol. Chem. 275, 7964–7974 (2000).

    CAS  PubMed  Google Scholar 

  27. Forster-Horvath, C. et al. Expression of CD44v3 protein in human endothelial cells in vitro and in tumoral microvessels in vivo. Microvasc. Res. 68, 110–118 (2004).

    CAS  PubMed  Google Scholar 

  28. Marr, H. S., Basalamah, M. A. & Edgell, C. J. Endothelial cell expression of testican mRNA. Endothelium 5, 209–219 (1997).

    CAS  PubMed  Google Scholar 

  29. BaSalamah, M. A., Marr, H. S., Duncan, A. W. & Edgell, C. J. Testican in human blood. Biochem. Biophys. Res. Commun. 283, 1083–1090 (2001).

    CAS  PubMed  Google Scholar 

  30. Beauvais, D. M. & Rapraeger, A. C. Syndecans in tumor cell adhesion and signaling. Reprod. Biol. Endocrinol. 2, 3 (2004).

    PubMed  PubMed Central  Google Scholar 

  31. Deepa, S. S., Yamada, S., Zako, M., Goldberger, O. & Sugahara, K. Chondroitin sulfate chains on syndecan-1 and syndecan-4 from normal murine mammary gland epithelial cells are structurally and functionally distinct and cooperate with heparan sulfate chains to bind growth factors. A novel function to control binding of midkine, pleiotrophin, and basic fibroblast growth factor. J. Biol. Chem. 279, 37368–37376 (2004).

    CAS  PubMed  Google Scholar 

  32. Halden, Y. et al. Interleukin-8 binds to syndecan-2 on human endothelial cells. Biochem. J. 377, 533–538 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hirschi, K. K. & D'Amore, P. A. Pericytes in the microvasculature. Cardiovasc. Res. 32, 687–698 (1996).

    CAS  PubMed  Google Scholar 

  34. Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nature Rev. Cancer 3, 422–433 (2003).

    CAS  Google Scholar 

  35. Erickson, A. C. & Couchman, J. R. Still more complexity in mammalian basement membranes. J. Histochem. Cytochem. 48, 1291–1306 (2000).

    CAS  PubMed  Google Scholar 

  36. Yurchenco, P. D., Amenta, P. S. & Patton, B. L. Basement membrane assembly, stability and activities observed through a developmental lens. Matrix Biol. 22, 521–538 (2004).

    CAS  PubMed  Google Scholar 

  37. Iozzo, R. V. Basement membrane proteoglycans: from cellar to ceiling. Nature Rev. Mol. Cell Biol. 6, 646–656 (2005).

    CAS  Google Scholar 

  38. Taipale, J. & Keski-Oja, J. Growth factors in the extracellular matrix. FASEB J. 11, 51–59 (1997).

    CAS  PubMed  Google Scholar 

  39. Schonherr, E. & Hausser, H. J. Extracellular matrix and cytokines: a functional unit. Dev. Immunol. 7, 89–101 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Lortat-Jacob, H., Grosdidier, A. & Imberty, A. Structural diversity of heparan sulfate binding domains in chemokines. Proc. Natl Acad. Sci. USA 99, 1229–1234 (2002). An important structural study showing that chemokines can bind to heparan sulphate by four different modes.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kawashima, H. et al. Collagen XVIII, a basement membrane heparan sulfate proteoglycan, interacts with L-selectin and monocyte chemoattractant protein-1. J. Biol. Chem. 278, 13069–13076 (2003).

    CAS  PubMed  Google Scholar 

  42. Celie, J. W. et al. Identification of L-selectin binding heparan sulfates attached to collagen type XVIII. J. Biol. Chem. 280, 26965–26973 (2005).

    CAS  PubMed  Google Scholar 

  43. Norgard-Sumnicht, K. E., Varki, N. M. & Varki, A. Calcium-dependent heparin-like ligands for L-selectin in nonlymphoid endothelial cells. Science 261, 480–483 (1993).

    CAS  PubMed  Google Scholar 

  44. Koenig, A., Norgard-Sumnicht, K., Linhardt, R. & Varki, A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. J. Clin. Invest. 101, 877–889 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Giuffre, L. et al. Monocyte adhesion to activated aortic endothelium: role of L-selectin and heparan sulfate proteoglycans. J. Cell. Biol. 136, 945–956 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Nelson, R. M. et al. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood 82, 3253–3258 (1993).

    CAS  PubMed  Google Scholar 

  47. Wang, L., Brown, J. R., Varki, A. & Esko, J. D. 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). Reports that heparin probably mediates its anti-inflammatory effects by binding to L- and P-selectin, with unique structural features of the heparin molecules being crucial for activity.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Xie, X. et al. Inhibition of selectin-mediated cell adhesion and prevention of acute inflammation by nonanticoagulant sulfated saccharides. Studies with carboxyl-reduced and sulfated heparin and with trestatin a sulfate. J. Biol. Chem. 275, 34818–34825 (2000).

    CAS  PubMed  Google Scholar 

  49. Wan, M. X., Zhang, X. W., Torkvist, L. & Thorlacius, H. Low molecular weight heparin inhibits tumor necrosis factor alpha-induced leukocyte rolling. Inflamm. Res. 50, 581–584 (2001).

    CAS  PubMed  Google Scholar 

  50. Luo, J., Kato, M., Wang, H., Bernfield, M. & Bischoff, J. Heparan sulfate and chondroitin sulfate proteoglycans inhibit E-selectin binding to endothelial cells. J. Cell. Biochem. 80, 522–531 (2001).

    CAS  PubMed  Google Scholar 

  51. Lowe, J. B. Glycosylation in the control of selectin counter-receptor structure and function. Immunol. Rev. 186, 19–36 (2002).

    CAS  PubMed  Google Scholar 

  52. Rosen, S. D. Ligands for L-selectin: homing, inflammation, and beyond. Annu. Rev. Immunol. 22, 129–156 (2004).

    CAS  PubMed  Google Scholar 

  53. Kawashima, H. et al. N-acetylglucosamine-6-O-sulfotransferases 1 and 2 cooperatively control lymphocyte homing through L-selectin ligand biosynthesis in high endothelial venules. Nature Immunol. 6, 1096–1104 (2005).

    CAS  Google Scholar 

  54. Uchimura, K. et al. A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases expressed in high endothelial venules. Nature Immunol. 6, 1105–1113 (2005). This study and reference 53 show that a sulphated ligand (6-sulpho sialyl Lewis X) is the dominant L-selectin ligand on HEVs.

    CAS  Google Scholar 

  55. Wang, L., Fuster, M., Sriramarao, P. & Esko, J. D. Endothelial heparan sulfate deficiency impairs L-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses. Nature Immunol. 6, 902–910 (2005). An important report showing that, unlike on HEVs, heparan sulphate is the main L-selectin ligand on the inflamed endothelium. It also clearly shows that endothelial-cell heparan sulphate binds and presents chemokines to leukocytes and is involved in chemokine transcytosis.

    CAS  Google Scholar 

  56. Gotte, M. et al. Role of syndecan-1 in leukocyte-endothelial interactions in the ocular vasculature. Invest. Ophthalmol. Vis. Sci. 43, 1135–1141 (2002).

    PubMed  Google Scholar 

  57. Gotte, M., Bernfield, M. & Joussen, A. M. Increased leukocyte-endothelial interactions in syndecan-1-deficient mice involve heparan sulfate-dependent and-independent steps. Curr. Eye Res. 30, 417–422 (2005).

    PubMed  Google Scholar 

  58. Xu, J., Park, P. W., Kheradmand, F. & Corry, D. B. Endogenous attenuation of allergic lung inflammation by syndecan-1. J. Immunol. 174, 5758–5765 (2005).

    CAS  PubMed  Google Scholar 

  59. Couchman, J. R. et al. Regulation of inositol phospholipid binding and signaling through syndecan-4. J. Biol. Chem. 277, 49296–49303 (2002).

    CAS  PubMed  Google Scholar 

  60. Lim, S. T., Longley, R. L., Couchman, J. R. & Woods, A. Direct binding of syndecan-4 cytoplasmic domain to the catalytic domain of protein kinase Cα (PKCα) increases focal adhesion localization of PKCα. J. Biol. Chem. 278, 13795–13802 (2003).

    CAS  PubMed  Google Scholar 

  61. Coombe, D. R., Watt, S. M. & Parish, C. R. 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).

    CAS  PubMed  Google Scholar 

  62. Diamond, M. S., Alon, R., Parkos, C. A., Quinn, M. T. & Springer, T. A. Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD1). J. Cell Biol. 130, 1473–1482 (1995).

    CAS  PubMed  Google Scholar 

  63. Gilat, D. et al. Molecular behavior adapts to context: heparanase functions as an extracellular matrix-degrading enzyme or as a T cell adhesion molecule, depending on the local pH. J. Exp. Med. 181, 1929–1934 (1995). A provocative study showing that the heparan-sulphate-degrading enzyme heparanase can, under certain circumstances, function as an adhesion molecule rather than an extracellular-matrix-degrading enzyme.

    CAS  PubMed  Google Scholar 

  64. Goldshmidt, O. et al. Cell surface expression and secretion of heparanase markedly promote tumor angiogenesis and metastasis. Proc. Natl. Acad. Sci. USA 99, 10031–10036 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Goldshmidt, O. et al. Heparanase mediates cell adhesion independent of its enzymatic activity. FASEB J. 17, 1015–1025 (2003).

    CAS  PubMed  Google Scholar 

  66. Sotnikov, I. et al. Enzymatically quiescent heparanase augments T cell interactions with VCAM-1 and extracellular matrix components under versatile dynamic contexts. J. Immunol. 172, 5185–5193 (2004).

    CAS  PubMed  Google Scholar 

  67. Handel, T. M., Johnson, Z., Crown, S. E., Lau, E. K. & Proudfoot, A. E. Regulation of protein function by glycosaminoglycans—as exemplified by chemokines. Annu. Rev. Biochem. 74, 385–410 (2005).

    CAS  PubMed  Google Scholar 

  68. Lau, E. K., Allen, S., Hsu, A. R. & Handel, T. M. Chemokine-receptor interactions: GPCRs, glycosaminoglycans and viral chemokine binding proteins. Adv. Protein Chem. 68, 351–391 (2004).

    CAS  PubMed  Google Scholar 

  69. Sadir, R., Imberty, A., Baleux, F. & Lortat-Jacob, H. 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).

    CAS  PubMed  Google Scholar 

  70. Webb, L. M., Ehrengruber, M. U., Clark-Lewis, I., Baggiolini, M. & Rot, A. Binding to heparan sulfate or heparin enhances neutrophil responses to interleukin 8. Proc. Natl Acad. Sci. USA 90, 7158–7162 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Hoogewerf, A. J. et al. Glycosaminoglycans mediate cell surface oligomerization of chemokines. Biochemistry 36, 13570–13578 (1997). The first study showing that heparan sulphate in solution and on cell surfaces can cause oligomerization of chemokines, a process that might be essential for optimum chemokine activity.

    CAS  PubMed  Google Scholar 

  72. Wagner, L. et al. β-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Nature 391, 908–911 (1998).

    CAS  PubMed  Google Scholar 

  73. Proudfoot, A. E. et al. Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc. Natl Acad. Sci. USA 100, 1885–1890 (2003). An elegant study showing that heparan sulphate binding and the resultant oligomerization is essential for the activity of some chemokines in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Johnson, Z. et al. Interference with heparin binding and oligomerization creates a novel anti-inflammatory strategy targeting the chemokine system. J. Immunol. 173, 5776–5785 (2004).

    CAS  PubMed  Google Scholar 

  75. Middleton, J., Patterson, A. M., Gardner, L., Schmutz, C. & Ashton, B. A. Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood 100, 3853–3860 (2002).

    CAS  PubMed  Google Scholar 

  76. Li, Q., Park, P. W., Wilson, C. L. & Parks, W. C. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111, 635–646 (2002).

    CAS  PubMed  Google Scholar 

  77. Shamri, R. et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nature Immunol. 6, 497–506 (2005).

    CAS  Google Scholar 

  78. Cinamon, G., Shinder, V. & Alon, R. Shear forces promote lymphocyte migration across vascular endothelium bearing apical chemokines. Nature Immunol. 2, 515–522 (2001).

    CAS  Google Scholar 

  79. Kohrgruber, N. et al. Plasmacytoid dendritic cell recruitment by immobilized CXCR3 ligands. J. Immunol. 173, 6592–6602 (2004).

    CAS  PubMed  Google Scholar 

  80. Miyasaka, M. & Tanaka, T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nature Rev. Immunol. 4, 360–370 (2004).

    CAS  Google Scholar 

  81. Middleton, J. et al. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91, 385–395 (1997). First demonstration that chemokines can be transported across an endothelial-cell barrier, bound to HSPGs, by a process known as transcytosis.

    CAS  PubMed  Google Scholar 

  82. Madri, J. A. & Graesser, D. Cell migration in the immune system: the evolving inter-related roles of adhesion molecules and proteinases. Dev. Immunol. 7, 103–116 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Duffy, M. J. Proteases as prognostic markers in cancer. Clin. Cancer Res. 2, 613–618 (1996).

    CAS  PubMed  Google Scholar 

  84. Nakajima, M., Irimura, T. & Nicolson, G. L. Heparanases and tumor metastasis. J. Cell. Biochem. 36, 157–167 (1988).

    CAS  PubMed  Google Scholar 

  85. Vlodavsky, I. et al. Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. Invasion Metastasis 12, 112–127 (1992).

    CAS  PubMed  Google Scholar 

  86. Vlodavsky, I. & Friedmann, Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J. Clin. Invest. 108, 341–347 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Parish, C. R., Freeman, C. & Hulett, M. D. Heparanase: a key enzyme involved in cell invasion. Biochim. Biophys. Acta 1471, M99–M108 (2001).

    CAS  PubMed  Google Scholar 

  88. Edovitsky, E. et al. Role of endothelial heparanase in delayed-type hypersensitivity. Blood 107, 3609–3616 (2006). A report indicating that heparanase derived from endothelial cells, rather than leukocytes, facilitates the entry of leukocytes into an inflammatory site.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Raats, C. J., Bakker, M. A., van den Born, J. & Berden, J. H. Hydroxyl radicals depolymerize glomerular heparan sulfate in vitro and in experimental nephrotic syndrome. J. Biol. Chem. 272, 26734–26741 (1997).

    CAS  PubMed  Google Scholar 

  90. Bartlett, M. R., Underwood, P. A. & Parish, C. R. 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).

    CAS  PubMed  Google Scholar 

  91. Sasaki, N., Higashi, N., Taka, T., Nakajima, M. & Irimura, T. Cell surface localization of heparanase on macrophages regulates degradation of extracellular matrix heparan sulfate. J. Immunol. 172, 3830–3835 (2004).

    CAS  PubMed  Google Scholar 

  92. Gingis-Velitski, S. et al. Heparanase uptake is mediated by cell membrane heparan sulfate proteoglycans. J. Biol. Chem. 279, 44084–44092 (2004).

    CAS  PubMed  Google Scholar 

  93. Chen, W. T. Membrane proteases: roles in tissue remodeling and tumour invasion. Curr. Opin. Cell Biol. 4, 802–809 (1992).

    CAS  PubMed  Google Scholar 

  94. Reiland, J. et al. Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion. J. Biol. Chem. 279, 8047–8055 (2004).

    CAS  PubMed  Google Scholar 

  95. Lider, O. et al. A disaccharide that inhibits tumor necrosis factor α is formed from the extracellular matrix by the enzyme heparanase. Proc. Natl Acad. Sci. USA 92, 5037–5041 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Patterson, A. M. et al. Induction of a CXCL8 binding site on endothelial syndecan-3 in rheumatoid synovium. Arthritis Rheum. 52, 2331–2342 (2005).

    CAS  PubMed  Google Scholar 

  97. Iozzo, R. V. & San Antonio, J. D. Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena. J. Clin. Invest. 108, 349–355 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Elenius, V., Gotte, M., Reizes, O., Elenius, K. & Bernfield, M. Inhibition by the soluble syndecan-1 ectodomains delays wound repair in mice overexpressing syndecan-1. J. Biol. Chem. 279, 41928–41935 (2004).

    CAS  PubMed  Google Scholar 

  99. Yuan, K., Hong, T. M., Chen, J. J., Tsai, W. H. & Lin, M. T. Syndecan-1 up-regulated by ephrinB2/EphB4 plays dual roles in inflammatory angiogenesis. Blood 104, 1025–1033 (2004).

    CAS  PubMed  Google Scholar 

  100. Fears, C. Y., Gladson, C. L. & Woods, A. Syndecan-2 is expressed in the microvasculature of gliomas and regulates angiogenic processes in microvascular endothelial cells. J. Biol. Chem. 281, 14533–14536 (2006).

    CAS  PubMed  Google Scholar 

  101. Ihrcke, N. S. & Platt, J. L. Shedding of heparan sulfate proteoglycan by stimulated endothelial cells: evidence for proteolysis of cell-surface molecules. J. Cell Physiol. 168, 625–637 (1996).

    CAS  PubMed  Google Scholar 

  102. Marshall, L. J., Ramdin, L. S. P., Brooks, T., Charlton, P. & Shute, J. K. 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).

    CAS  PubMed  Google Scholar 

  103. Asundi, V. K., Erdman, R., Stahl, R. C. & Carey, D. J. Matrix metalloproteinase-dependent shedding of syndecan-3, a transmembrane heparan sulfate proteoglycan, in Schwann cells. J. Neurosci. Res. 73, 593–602 (2003).

    CAS  PubMed  Google Scholar 

  104. Ding, K., Lopez-Burks, M., Sanchez-Duran, J. A., Korc, M. & Lander, A. D. Growth factor-induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells. J. Cell Biol. 171, 729–738 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Wang, Z., Gotte, M., Bernfield, M. & Reizes, O. Constitutive and accelerated shedding of murine syndecan-1 is mediated by cleavage of its core protein at a specific juxtamembrane site. Biochemistry 44, 12355–12361 (2005).

    CAS  PubMed  Google Scholar 

  106. Brown, K. J. & Parish, C. R. Histidine-rich glycoprotein and platelet factor 4 mask heparan sulfate proteoglycans recognized by acidic and basic fibroblast growth factor. Biochemistry 33, 13918–13927 (1994).

    CAS  PubMed  Google Scholar 

  107. Perollet, C., Han, Z. C., Savona, C., Caen, J. P. & Bikfalvi, A. Platelet factor 4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization. Blood 91, 3289–3299 (1998).

    CAS  PubMed  Google Scholar 

  108. Freeman, C. & Parish, C. R. A rapid quantitative assay for the detection of mammalian heparanase activity. Biochem. J. 325, 229–237 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Jones, A. L., Hulett, M. D. & Parish, C. R. Histidine-rich glycoprotein: a novel adaptor protein in plasma that modulates the immune, vascular and coagulation systems. Immunol. Cell Biol. 83, 106–118 (2005).

    CAS  PubMed  Google Scholar 

  110. Chelmicka-Szorc, E. & Arnason, B. G. Partial suppression of experimental allergic encephalomyelitis with heparin. Arch. Neurol. 27, 153–158 (1972).

    CAS  PubMed  Google Scholar 

  111. Willenborg, D. O. & Parish, C. R. Inhibition of allergic encephalomyelitis in rats by treatment with sulfated polysaccharides. J. Immunol. 140, 3401–3405 (1988).

    CAS  PubMed  Google Scholar 

  112. Lider, O. et al. Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparins. J. Clin. Invest. 83, 752–756 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Diamant, Z. et al. Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma. Am. J. Respir. Crit. Care Med. 153, 1790–1795 (1996).

    CAS  PubMed  Google Scholar 

  114. Sy, M. S. et al. Inhibition of delayed-type hypersensitivity by heparin depleted of anticoagulant activity. Cell. Immunol. 82, 23–32 (1983).

    CAS  PubMed  Google Scholar 

  115. Lider, O. et al. Inhibition of T lymphocyte heparanase by heparin prevents T cell migration and T cell-mediated immunity. Eur. J. Immunol. 20, 493–499 (1990).

    CAS  PubMed  Google Scholar 

  116. Lever, R. & Page, C. P. Novel drug development opportunities for heparin. Nature Rev. Drug Discov. 1, 140–148 (2002).

    CAS  Google Scholar 

  117. Capila, I. & Linhardt, R. J. Heparin-protein interactions. Angew. Chem. Int. Ed. Engl. 41, 391–412 (2002).

    PubMed  Google Scholar 

  118. Parish, C. R., Freeman, C., Brown, K. J., Francis, D. J. & Cowden, W. B. Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res. 59, 3433–3441 (1999).

    CAS  PubMed  Google Scholar 

  119. Khachigian, L. M. & Parish, C. R. Phosphomannopentaose sulfate (PI-88): heparan sulfate mimetic with clinical potential in multiple vascular pathologies. Cardiovasc. Drug Rev. 22, 1–6 (2004).

    CAS  PubMed  Google Scholar 

  120. Ishida, K. et al. Structure-based design of a selective heparanase inhibitor as an antimetastatic agent. Mol. Cancer Ther. 3, 1069–1077 (2004).

    CAS  PubMed  Google Scholar 

  121. Ferro, V., Hammond, E. & Fairweather, J. K. The development of inhibitors of heparanase, a key enzyme involved in tumour metastasis, angiogenesis and inflammation. Mini Rev. Med. Chem. 4, 693–702 (2004).

    CAS  PubMed  Google Scholar 

  122. Freeman, C. et al. Use of sulfated linked cyclitols as heparan sulfate mimetics to probe the heparin/heparan sulfate binding specificity of proteins. J. Biol. Chem. 280, 8842–8849 (2005). The use of a family of heparan-sulphate mimetics to show that a range of heparan-sulphate-binding proteins interact with different structural motifs in heparan sulphate.

    CAS  PubMed  Google Scholar 

  123. Karoli, T. et al. Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88). J. Med. Chem. 48, 8229–8236 (2005).

    CAS  PubMed  Google Scholar 

  124. Fernandez-Botran, R. et al. Targeting of glycosaminoglycan-cytokine interactions as a novel therapeutic approach in allotransplantation. Transplantation 74, 623–629 (2002).

    CAS  PubMed  Google Scholar 

  125. Fridman, R. et al. Soluble antigen induces T lymphocytes to secrete an endoglycosidase that degrades the heparan sulfate moiety of subendothelial extracellular matrix. J. Cell. Physiol. 130, 85–92 (1987).

    CAS  PubMed  Google Scholar 

  126. Iozzo, R. V. Heparan sulfate proteoglycans: intricate molecules with intriguing functions. J. Clin. Invest. 108, 165–167 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Rapraeger, A., Jalkanen, M., Endo, E., Koda, J. & Bernfield, M. The cell surface proteoglycan from mouse mammary epithelial cells bears chondroitin sulfate and heparan sulfate glycosaminoglycans. J. Biol. Chem. 260, 11046–11052 (1985).

    CAS  PubMed  Google Scholar 

  128. Shworak, N. W., Shirakawa, M., Mulligan, R. C. & Rosenberg, R. D. Characterization of ryudocan glycosaminoglycan acceptor sites. J. Biol. Chem. 269, 21204–21214 (1994).

    CAS  PubMed  Google Scholar 

  129. Kaneider, N. C. et al. Expression and function of syndecan-4 in human platelets. Thromb. Haemost. 93, 1120–1127 (2005).

    CAS  PubMed  Google Scholar 

  130. Feistritzer, C., Kaneider, N. C., Sturn, D. H. & Wiedermann, C. J. Syndecan-4-dependent migration of human eosinophils. Clin. Exp. Allergy 34, 696–703 (2004).

    CAS  PubMed  Google Scholar 

  131. Yeaman, C. & Rapraeger, A. C. Membrane-anchored proteoglycans of mouse macrophages: P388D1 cells express a syndecan-4-like heparan sulfate proteoglycan and a distinct chondroitin sulfate form. J. Cell Physiol. 157, 413–425 (1993).

    CAS  PubMed  Google Scholar 

  132. Zhang, Y., Pasparakis, M., Kollias, G. & Simons, M. Myocyte-dependent regulation of endothelial cell syndecan-4 expression. Role of TNF-α. J. Biol. Chem. 274, 14786–14790 (1999).

    CAS  PubMed  Google Scholar 

  133. Srivastava, M. et al. The inflammatory versus constitutive trafficking of mononuclear phagocytes into the alveolar space of mice is associated with drastic changes in their gene expression profiles. J. Immunol. 175, 1884–1893 (2005).

    CAS  PubMed  Google Scholar 

  134. Manakil, J. F., Sugerman, P. B., Li, H., Seymour, G. J. & Bartold, P. M. Cell-surface proteoglycan expression by lymphocytes from peripheral blood and gingiva in health and periodontal disease. J. Dent. Res. 80, 1704–1710 (2001).

    CAS  PubMed  Google Scholar 

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Acknowledgements

C.R.P. is supported by the Australian National Health and Medical Research Council.

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  1. Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia

    Christopher R. Parish

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Glossary

G-protein-coupled receptor

(GPCR). A receptor that is composed of seven membrane-spanning helical segments. These receptors associate with G-proteins, which are a family of trimeric intracellular-signalling proteins with common β- and γ-chains, and one of several α-chains. The α-chain determines the nature of the signal that is transmitted from a ligand-occupied GPCR to downstream effector systems.

Tight junction

A ring of proteins that seals apical epithelium. Tight junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zona occludens proteins.

Polyanionic

A molecule that has many negatively charged chemical entities attached, the most common being negatively charged carboxyl, sulphate and phosphate groups.

Pericytes

Cells embedded in the vascular basement membrane of microvessels that are thought to be derived from the vascular smooth muscle lineage. They make close cellular contact with endothelial cells and this interaction is essential for the maintenance of vessel function, as well as for the regulation of angiogenesis and vascular remodelling.

Intravital microscopy

This is used for examination of biological processes, such as leukocyte–endothelial-cell interactions, in living tissue. In general, translucent tissues are used, such as the mesentery or cremaster muscle, which can be exposed and mounted for microscopic observation.

Sialylated

A molecule that has the monosaccharide sialic acid (also known as neuraminic acid) covalently attached. Most of the sialic-acid residues are attached to the non-reducing termini of oligosaccharide chains linked to proteins or lipids.

Fucosylated

A molecule that has the monosaccharide L-fucose covalently attached, which is normally a terminal rather than an intra-chain residue in carbohydrates. L-Fucose is usually associated with oligosaccharide chains linked to proteins or lipids.

High endothelial venules

(HEVs). HEVs are specialized post-capillary venules in lymphoid organs through which lymphocytes enter. L-selectin plays an essential part in this entry process by mediating the initial interaction of lymphocytes with HEVs.

Transcytosis

The process of transport of material across a cell layer by uptake on one side of the cell into a coated vesicle. The vesicle might then be sorted through the trans-Golgi network and transported to the opposite side of the cell.

Immuno-electron microscopy

A procedure that uses antibodies, usually coupled to electron-dense particles such as colloidal gold, to determine the location of molecules on the cell surface and in cells at the electron-microscopic level.

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Parish, C. The role of heparan sulphate in inflammation. Nat Rev Immunol 6, 633–643 (2006). https://doi.org/10.1038/nri1918

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