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Translocation of Active Heparanase to Cell Surface Regulates Degradation of Extracellular Matrix Heparan Sulfate upon Transmigration of Mature Monocyte-Derived Dendritic Cells¹

Sandrine Benhamron^*,, Hovav Nechushtan, Inna Verbovetski^*, Alon Krispin^*, Ghada Abboud-Jarrous, Eyal Zcharia, Evgeny Edovitsky, Efrat Nahari^*, Tamar Peretz, Israel Vlodavsky and Dror Mevorach^2,*

Laboratories for ^* Cellular and Molecular Immunology and Oncology, Hadassah-Hebrew University, and Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Israel

After Ag capture and exposure to danger stimuli, maturing dendritic cells (DCs) migrate to regional lymph nodes, where antigenic peptides are presented to T lymphocytes. To migrate from peripheral tissue such as the epidermis to regional lymph nodes, Ag-bearing epidermal Langerhans cells must move through an extracellular matrix (ECM) of various compositions. The nature of their capacity to transmigrate via ECM is not well understood, although MIP-3 and CCR7 play critical roles. We were interested in verifying whether heparanase, a heparan sulfate-degrading endo--D-glucuronidase that participates in ECM degradation and remodeling, is expressed and functional in monocyte-derived DCs. Using immunohistochemistry, confocal microscopy, RT-PCR, Western blot analysis, assays for heparanase activity, and Matrigel transmigration, we show that heparanase is expressed in both nuclei and cytoplasm of immature DCs, and that gene expression and synthesis take place mainly in monocytes and early immature DCs. We also found that both nuclear and cytoplasm fractions show heparanase activity, and upon LPS-induced maturation, heparanase translocates to the cell surface and degrades ECM heparan sulfate. Matrigel transmigration assays showed a MIP-3-comparable role for heparanase. Because heparan sulfate glycosaminoglycans play a key role in the self-assembly, insolubility, and barrier properties of the ECM, the results of this study suggest that heparanase is a key enzyme in DC transmigration through the ECM.

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