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¹ Children's Hospital, University of Heidelberg, 69120 Heidelberg, Germany
² Institute of Molecular Cardiovascular Research, RWTH Aachen, 52074 Aachen, Germany
³ Max-Planck-Institute for Molecular Biomedicine, 48149 Muenster, Germany
⁴ La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037
⁵ Department of Pathology and ⁶ Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093
⁷ Institute of Biochemistry, University of Leipzig, 04103 Leipzig, Germany
⁸ Max-Planck-Institute for Biochemistry, 82152 Martinsried, Germany
⁹ Department of Anesthesiology and Critical Care Medicine, University of Muenster, 48149 Muenster, Germany
¹⁰ Dr. v. Haunersches Children's Hospital, Ludwig-Maximilians-Universität, 80336 Munich, Germany
¹¹ Research Center Borstel, 23845 Borstel, Germany
¹² Walter Brendel Center for Experimental Medicine, Ludwig-Maximilians-Universität, 81377 Munich, Germany

CORRESPONDENCE Markus Sperandio: markus.sperandio{at}med.uni-muenchen.de

Recent in vitro studies have suggested a role for sialylation in chemokine receptor binding to its ligand (Bannert, N., S. Craig, M. Farzan, D. Sogah, N.V. Santo, H. Choe, and J. Sodroski. 2001. J. Exp. Med. 194:1661–1673). This prompted us to investigate chemokine-induced leukocyte adhesion in inflamed cremaster muscle venules of 2,3 sialyltransferase (ST3Gal-IV)-deficient mice. We found a marked reduction in leukocyte adhesion to inflamed microvessels upon injection of the CXCR2 ligands CXCL1 (keratinocyte-derived chemokine) or CXCL8 (interleukin 8). In addition, extravasation of ST3Gal-IV^–/– neutrophils into thioglycollate-pretreated peritoneal cavities was significantly decreased. In vitro assays revealed that CXCL8 binding to isolated ST3Gal-IV^–/– neutrophils was markedly impaired. Furthermore, CXCL1-mediated adhesion of ST3Gal-IV^–/– leukocytes at physiological flow conditions, as well as transendothelial migration of ST3Gal-IV^–/– leukocytes in response to CXCL1, was significantly reduced. In human neutrophils, enzymatic desialylation decreased binding of CXCR2 ligands to the neutrophil surface and diminished neutrophil degranulation in response to these chemokines. In addition, binding of 2,3-linked sialic acid–specific Maackia amurensis lectin II to purified CXCR2 from neuraminidase-treated CXCR2-transfected HEK293 cells was markedly impaired. Collectively, we provide substantial evidence that sialylation by ST3Gal-IV significantly contributes to CXCR2-mediated leukocyte adhesion during inflammation in vivo.

Abbreviations used: CF-CXCL8, human carboxyfluorescein-labeled CXCL8; fMLP, N-formyl-Met-Leu-Phe; GPCR, G_i protein–coupled receptor; ICAM-1, intercellular adhesion molecule 1; MAL-II, Maackia amurensis lectin II; PTx, pertussis toxin; ST3Gal-IV, 2,3 sialyltransferase; WBC, white blood cell.

D. Frommhold and A. Ludwig contributed equally to this work.

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