The Journal of Experimental Medicine
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Published 19 May 2003. doi:10.1084/jem.20021854
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© Rockefeller University Press, 0022-1007/2003/5/1355 $5.00
The Journal of Experimental Medicine, Volume 197, Number 10, 1355-1363

P-selectin Glycoprotein Ligand-1 Mediates L-Selectin–dependent Leukocyte Rolling in Venules

Markus Sperandio1,3, Michael L. Smith1, S. Bradley Forlow1, Timothy S. Olson2, Lijun Xia3, Rodger P. McEver3,4 and Klaus Ley1,2

1 Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908
2 Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908
3 Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation
4 Department of Biochemistry and Molecular Biology, Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104

Address correspondence to Klaus Ley, University of Virginia Health System, Cardiovascular Research Center, MR5 Bldg, Rm. 1013, P.O. Box 801 394, Charlottesville, VA 22908-1394. Phone: 434-243-9966; Fax: 434-982-3870; E-mail: klausley{at}virginia.edu

Leukocyte rolling in postcapillary venules of inflamed tissues is reduced in L-selectin–deficient mice and mice treated with L-selectin blocking antibodies, but the glycoprotein ligand for L-selectin in inflamed venules is unknown. Here, we show that L-selectin–dependent rolling after P-selectin blockade is completely absent in P-selectin glycoprotein ligand-1 (PSGL-1)-/- mice or wild-type mice treated with a PSGL-1 blocking monoclonal antibody. Immunohistochemistry and flow cytometry failed to show PSGL-1 expression on resting or inflamed endothelium or on platelets. To investigate whether leukocyte-expressed PSGL-1 is mediating L-selectin–dependent rolling, we reconstituted lethally irradiated wild-type mice with PSGL-1-/- bone marrow cells. These chimeric mice showed no L-selectin–dependent rolling, suggesting that leukocyte-expressed PSGL-1 mediates L-selectin–dependent rolling. Frame-to-frame video analysis of L-selectin–dependent rolling in wild-type mice showed that the majority of observed L-selectin–dependent leukocyte rolling was between free flowing leukocytes and already adherent leukocytes or possibly leukocyte fragments, followed by E-selectin–dependent leukocyte rolling along the endothelium. Leukocyte rolling was significantly slower for leukocyte–endothelial than leukocyte–leukocyte interactions. We conclude that leukocyte-expressed PSGL-1 serves as the main L-selectin ligand in inflamed postcapillary venules. L-selectin binding to PSGL-1 initiates tethering events that enable L-selectin–independent leukocyte-endothelial interactions. These findings provide a molecular mechanism for the inflammatory defects seen in L-selectin–deficient mice.

Key Words: PSGL-1 • L-selectin • inflammation • leukocyte rolling • intravital


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