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J. Biol. Chem., Vol. 282, Issue 7, 4812-4820, February 16, 2007

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Mechanical Shedding of L-selectin from the Neutrophil Surface during Rolling on Sialyl Lewis x under Flow^*

Dooyoung Lee, Joanne B. Schultz, Philip A. Knauf, and Michael R. King^¶1

From the Departments of Chemical Engineering, Biochemistry and Biophysics, and ^¶Biomedical Engineering, University of Rochester, Rochester, New York 14642

The interaction of L-selectin expressed on leukocytes with endothelial cells leads to capture and rolling and is critical for the recruitment of leukocytes into sites of inflammation. It is known that leukocyte activation by chemoattractants, the change of osmotic pressure in cell media, or cross-linking of L-selectin all result in rapid shedding of L-selectin. Here we present a novel mechanism for surface cleavage of L-selectin on neutrophils during rolling on a sialyl Lewis x-coated surface that involves mechanical force. Flow cytometry and rolling of neutrophils labeled with Qdot®-L-selectin antibodies in an in vitro flow chamber showed that the mechanical shedding of L-selectin occurs during rolling and depends on the amount of shear applied. In addition, the mechanical L-selectin shedding causes an increase in cell rolling velocity with rolling duration, suggesting a gradual loss of L-selectin and is mediated by p38 mitogen-activated protein kinase activation. Thus, these data show that mechanical force induces the cleavage of L-selectin from the neutrophil surface during rolling and therefore decreases the adhesion of cells to a ligand-presenting surface in flow.

Received for publication, October 25, 2006 , and in revised form, December 11, 2006.

We dedicate this article to our beloved colleague Prof. Phil Knauf, who lost a courageous battle with cancer after the completion of this study.

^* This work was supported by Grant HL018208 from the National Institutes of Health (to M. R. K. and P. A. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biomedical Engineering, University of Rochester, 601 Elmwood Ave., Box 639, Rochester, NY 14642-8639. Tel.: 585-275-3285; Fax: 585-273-4746; E-mail: mike_king{at}urmc.rochester.edu.

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