The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/12/1769/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 12, December 20, 1999 1769-1782

Original Article

Targeted Gene Disruption Demonstrates That P-Selectin Glycoprotein Ligand 1 (PSGL-1) Is Required for P-Selectin–mediated but Not E-Selectin–mediated Neutrophil Rolling and Migration

Jing Yanga,b, Takako Hirataa,b, Kevin Crocea,b, Glenn Merrill-Skoloffa,b, Boris Tchernycheva,b, Eric Williamsa,b, Robert Flaumenhafta,b, Barbara C. Furiea,b, and Bruce Furiea,b
a Center for Hemostasis and Thrombosis Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215
b Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111

Correspondence to: Bruce Furie, Beth Israel Deaconess Cancer Center, Kirstein 153, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Tel:617-667-0620 Fax:617-975-8030 E-mail:bfurie{at}caregroup.harvard.edu.

P-selectin glycoprotein ligand 1 (PSGL-1) is a mucin-like selectin counterreceptor that binds to P-selectin, E-selectin, and L-selectin. To determine its physiological role in cell adhesion as a mediator of leukocyte rolling and migration during inflammation, we prepared mice genetically deficient in PSGL-1 by targeted disruption of the PSGL-1 gene. The homozygous PSGL-1–deficient mouse was viable and fertile. The blood neutrophil count was modestly elevated. There was no evidence of spontaneous development of skin ulcerations or infections. Leukocyte infiltration in the chemical peritonitis model was significantly delayed. Leukocyte rolling in vivo, studied by intravital microscopy in postcapillary venules of the cremaster muscle, was markedly decreased 30 min after trauma in the PSGL-1–deficient mouse. In contrast, leukocyte rolling 2 h after tumor necrosis factor {alpha} stimulation was only modestly reduced, but blocking antibodies to E-selectin infused into the PSGL-1–deficient mouse almost completely eliminated leukocyte rolling. These results indicate that PSGL-1 is required for the early inflammatory responses but not for E-selectin–mediated responses. These kinetics are consistent with a model in which PSGL-1 is the predominant neutrophil P-selectin ligand but is not a required counterreceptor for E-selectin under in vivo physiological conditions.

Key Words: selectin, leukocyte rolling, cell adhesion, P-selectin, E-selectin


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