Heparanase regulates immune cell functions

Immune cells can modify surrounding extracellular matrices by producing matrix degradation enzymes. Heparan sulfate proteoglycans, a major component of basement membrane, play a key role in the self-assembly, insolubility, and barrier properties of the matrix. Some immune cell subsets express heparanase, the sole mammalian endoglycosidase that cleaves heparan sulfate chains and thereby potentially modulates integrity of basement membrane. Other potential substrates of heparanase are sulfated glycans expressed in the cell bodies such as heparin proteoglycans accumulated in secretory granules of mast cells. Physiological relevance of heparanase action, cleavage of sulfated glycans in extracellular matrix and granular components, has not been intensively studied in the context of immunology. In the present study, we focus on the following aspects of the heparanase action. (a) Regulated heparanase action in leukocyte extravasation [1, 2]: Monocytes and neutrophils transmigrate across subendothelial basement membrane during extravasation, however mechanism to facilitate the dynamic movement, including cellular machinery of heparanase action, has not been clarified. Topical administration of a heparanase inhibitor SF-4 [3] significantly reduced the number of infiltrated leukocytes into inflamed air pouches. As for U937 human monocyte-like cells, cell surface heparanase was capped when they were allowed to adhere. A chemoattractant-dependent polarization of the cells resulted in heparanase redistribution at the leading edge of migration. Thus we propose that heparanase action in the leukocytes is regulated in a spaciotemporal manner to avoid excessive tissue damage. (b) Heparanase-dependent cleavage of mast cell heparin proteoglycan [2, 4]: Macromolecular heparin in connective tissue-type mast cells is cleaved into smaller fragments during the biosynthesis, however, consequent changes in mast cell function are unknown. A connective tissue-type mast cell line MST transfected with heparanase cDNA accumulated active form of heparanase in the secretory granules. The resultant heparin downsizing altered the amount of accumulated heparin in the granules and mobility of granular contents in the extracellular matrix where mast cells were distributed. References 1. Sasaki N et al. (2004) J Immunol 172: 3830-3835. 2. Komatsu N et al. (2008) J Immunol Methods 331: 82-93. 3. Nishimura Y et al. (2000) J Org Chem 65: 2-11. 4. Higashi N et al. submitted. L10.2