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  3. An iminosugar-based heparanase inhibitor heparastatin (SF4) suppresses infiltration of neutrophils and monocytes into inflamed dorsal air pouches

An iminosugar-based heparanase inhibitor heparastatin (SF4) suppresses infiltration of neutrophils and monocytes into inflamed dorsal air pouches

  • Int Immunopharmacol. 2016 Jun;35:15-21. doi: 10.1016/j.intimp.2016.03.017.
Mayumi Sue 1,  Nobuaki Higashi 2,  Hiroaki Shida 1,  Yusuke Kogane 1,  Yoshio Nishimura 3,  Hayamitsu Adachi 3,  Elzbieta Kolaczkowska 4,  Magdalena Kepka 4,  Motowo Nakajima 5,  Tatsuro Irimura 6
Affiliations

Affiliations

  • 1 Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 2 Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; One-stop Sharing Facility Center for Future Drug Discoveries, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: higashi@mol.f.u-tokyo.ac.jp.
  • 3 Institute of Microbial Chemistry (BIKAKEN), Kamiosaki 3-14-23, Shinagawa-ku, Tokyo 141-0021, Japan.
  • 4 Institute of Zoology, Jagiellonian University, ul. Gronostajowa 9, 30-387 Krakow, Poland.
  • 5 SBI Pharmaceuticals Co., Ltd., 1-6-1, Roppongi, Minato-ku, Tokyo 106-6019, Japan.
  • 6 Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Biochemistry, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 104-8560, Japan; Department of Breast and Endocrine Surgery, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 104-8560, Japan. Electronic address: t-irimura@juntendo.ac.jp.
PMID: 27015605 DOI: 10.1016/j.intimp.2016.03.017
Abstract

Local infiltration of inflammatory cells is regulated by a number of biological steps during which the cells likely penetrate through subendothelial basement membranes that contain heparan sulfate proteoglycans. In the present study, we examined whether administration of heparastatin (SF4), an iminosugar-based inhibitor of heparanase, could suppress local inflammation and degradation of heparan sulfate proteoglycans in basement membranes. In a carrageenan- or formyl peptide-induced dorsal air pouch inflammation model, the number of infiltrated neutrophils and monocytes was significantly lower in mice after topical administration of heparastatin (SF4). The concentration of chemokines MIP-2 and KC in pouch exudates of drug-treated mice was similar to control. In a zymosan-induced peritonitis model, the number of infiltrated cells was not altered in drug-treated mice. To further test how heparastatin (SF4) influences transmigration of inflammatory neutrophils, its suppressive effect on migration and matrix degradation was examined in vitro. In the presence of heparastatin (SF4), the number of neutrophils that infiltrated across a Matrigel-coated polycarbonate membrane was significantly lower, while the number of neutrophils passing through an uncoated membrane was not altered. Lysate of bone marrow-derived neutrophils released sulfate-radiolabeled macromolecules from basement membrane-like extracellular matrix, which was suppressed by heparastatin (SF4). Heparan sulfate degradation activity was almost completely abolished after incubation of lysate with protein G-conjugated anti-heparanase monoclonal antibody, strongly suggesting that the activity was due to heparanase-mediated degradation. Taken together, in a dorsal air pouch inflammation model heparastatin (SF4) potentially suppresses extravasation of inflammatory cells by impairing the degradation of basement membrane heparan sulfate.

Keywords

Chemokines; Extracellular matrix; Heparanase; Heparastatin (SF4).

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