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

Abstract

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 α 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.

The α(1,3)-Fucosyltransferase Fuc-TIV, but Not Fuc-TVII, Generates Sialyl Lewis X-like Epitopes Preferentially on Glycolipids

“…Antibodies against mouse PSGL-1 inhibit neutrophil recruitment into inflamed peritoneum (30), and the migration of Th1 cells into inflamed skin (6). Similar results were obtained with mice deficient for the PSGL-1 gene (31,32).…”

Platelets stimulated by IgG-coated surfaces bind and activate neutrophils through a selectin-dependent pathway

“…Such data argue for integrin-independent mechanisms. P-selectin promotes the accumulation and emigration of neutrophils during inflammation and thrombosis [16], and its ligand PSGL-1 is probably very important for the early neutrophil activation, including rolling along endothelial P-selectin [36,37]. The results in this study suggest a major contribution of platelet derived components to trigger the P-selectin/PSGL-1 interaction.…”

Endoglycan, a Member of the CD34 Family, Functions as an L-selectin Ligand through Modification with Tyrosine Sulfation and Sialyl Lewis x

“…If it is found that P-selectin and E-selectin can utilize endoglycan as a ligand, as is strongly suspected from its parallels to PSGL-1, the range of potential in vivo functions for this molecule would be further broadened since these selectins are found on platelets and/or activated vascular endothelium. Gene targeting approaches (52,53) and antibody blockade studies (49) have been essential in establishing the importance of PSGL-1 as a selectin ligand. Similar approaches will be necessary to gain a further understanding of endoglycan.…”