title: Enzymatically quiescent heparanase augments T cell interactions with VCAM-1 and extracellular matrix components under versatile dynamic contexts.
abstract: During their migration into inflammatory sites, immune cells, such as T cells, secrete extracellular matrix (ECM)-degrading enzymes, such as heparanase, which, under mildly acidic conditions, degrade heparan sulfate proteoglycans (HSPG). We have previously shown that at pH 7.2, human placental heparanase loses its enzymatic activity, while retaining its ability to bind HSPG and promote T cell adhesion to unfractionated ECM. We now demonstrate that the 65-kDa recombinant human heparanase, which is devoid of enzymatic activity, but can still bind HSPG, captures T cells under shear flow conditions and mediates their rolling and arrest, in the absence or presence of stromal cell-derived factor 1 alpha (SDF-1 alpha; CXCL12), in an alpha(4)beta(1)-VCAM-1-dependent manner. Furthermore, heparanase binds to and induces T cell adhesion to key ECM components, like fibronectin and hyaluronic acid, in beta(1) integrin- and CD44-specific manners, respectively, via the activation of the protein kinase C and phosphatidylinositol 3-kinase intracellular signaling machineries. Although the nature of the putative T cell heparanase-binding moiety is unknown, it appears that heparanase exerts its proadhesive activity by interacting with the T cells' surface HSPG, because pretreatment of the cells with heparinase abolished their subsequent response to heparanase. Also, heparanase augmented the SDF-1 alpha-triggered phosphorylation of Pyk-2 and extracellular signal-regulated kinase-2 implicated in integrin functioning. Moreover, heparanase, which had no chemotactic effect on T cells on its own, augmented the SDF-1 alpha-induced T cell chemotaxis across fibronectin. These findings add another dimension to the known versatility of heparanase as a key regulator of T cell activities during inflammation, both in the context of the vasculature and at extravascular sites.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ilya
authors.initials: I
authors.lastname: Sotnikov
authors.forename: Rami
authors.initials: R
authors.lastname: Hershkoviz
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.forename: Liora
authors.initials: L
authors.lastname: Cahalon
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
authors.forename: Ofer
authors.initials: O
authors.lastname: Lider
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D024141:Collagen Type IV / Q000502:physiology; D005109:Extracellular Matrix / Q000201:enzymology* / Q000276:immunology* / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism / Q000502:physiology; D051418:Focal Adhesion Kinase 2; D005966:Glucuronidase / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006820:Hyaluronic Acid / Q000502:physiology; D007399:Interphase / Q000276:immunology; D036904:Leukocyte Rolling / Q000276:immunology; D008213:Lymphocyte Activation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000276:immunology; D013379:Substrate Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology*; D000099175:Heparanase
chemical_list: D000276:Adjuvants, Immunologic; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D024141:Collagen Type IV; D005353:Fibronectins; D051418:Focal Adhesion Kinase 2; D005966:Glucuronidase; D006820:Hyaluronic Acid; D020928:Mitogen-Activated Protein Kinases; D011505:Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D000099175:Heparanase; C515255:CXCL12 protein, human