P-selectin glycoprotein ligand-1–deficient mice have impaired leukocyte tethering to E-selectin under flow

Abstract

P-selectin glycoprotein ligand-1 (PSGL-1) mediates rolling of leukocytes on P-selectin under flow. The glycoproteins that enable leukocyte tethering to or rolling on E-selectin are not known. We used gene targeting to prepare PSGL-1-deficient (PSGL-1 -/-) mice, which were healthy but had moderately elevated total blood leukocytes. Fluid-phase E-selectin bound to approximately 70% fewer sites on PSGL-1 -/-than PSGL-1 +/+ neutrophils. Compared with PSGL-1 +/+ leukocytes, significantly fewer PSGL-1 -/-leukocytes rolled on E-selectin in vitro, because their initial tethering to E-selectin was impaired. The residual cells that tethered rolled with the same shear resistance and velocities as PSGL-1 +/+ leukocytes. Compared with PSGL-1 +/+ mice, significantly fewer PSGL-1 -/-leukocytes rolled on E-selectin in TNF--treated venules of cremaster muscle in which P-selectin function was blocked by an mAb. The residual PSGL-1 -/-leukocytes that tethered rolled with slow velocities equivalent to those of PSGL-1 +/+ leukocytes. These results reveal a novel function for PSGL-1 in tethering leukocytes to E-selectin under flow.