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

P-selectin glycoprotein ligand 1 (PSGL-1) is a mucin-like selectin counterr eceptor 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 i n PSGL-1 by targeted disruption of the PSGL-1 gene. The homozygous PSGL-1-d eficient mouse was viable and fertile. The blood neutrophil count was modes tly elevated. There was no evidence of spontaneous development of skin ulce rations or infections. Leukocyte infiltration in the chemical peritonitis m odel was significantly delayed. Leukocyte rolling in vivo, studied by intra vital microscopy in postcapillary venules of the cremaster muscle, was mark edly decreased 30 min after trauma in the PSGL-1-deficient mouse. In contra st, leukocyte rolling 2 h after tumor necrosis factor or stimulation was on ly modestly reduced, but blocking antibodies to E-selectin infused into the PSGL-1-deficient mouse almost completely eliminated leukocyte rolling. The se results indicate that PSGL-1 is required for the early inflammatory resp onses but not for E-selectin-mediated responses. These kinetics are consist ent with a model in which PSGL-1 is the predominant neutrophil P-selectin l igand but is not a required counterreceptor for E-selectin under in vivo ph ysiological conditions.