P-Selectin Glycoprotein Ligand-1 Regulates Adhesive Properties of the Endothelium and Leukocyte Trafficking Into Adipose Tissue

Abstract

Adhesive interactions between endothelial cells and leukocytes affect leukocyte trafficking in adipose tissue. The role of P-selectin glycoprotein ligand-1 (Psgl-1) in this process is unclear. The goal of this study was to determine the effect of Psgl-1 deficiency on adhesive properties of the endothelium and on leukocyte recruitment into obese adipose depots. A genetic model of obesity was generated to study the effects of Psgl-1 deficiency on leukocyte trafficking. Leukocyte-endothelial interactions were increased in obese leptin receptor mutant mice (Lepr(db/db),Psgl-1(+/+)) but not obese Psgl-1-deficient mice (Lepr(db/db),Psgl-1(-/-)), when compared with lean mice (Lepr(+/+),Psgl-1(+/+)). This effect of Psgl-1 deficiency was due to indirect effects of Psgl-1, because Psgl-1(+/+) adoptively transferred leukocytes did not exhibit enhanced rolling in Lepr (db/db),Psgl-1(-/-) mice. Additionally, circulating levels of P-selectin, E-selectin, monocyte chemoattractant protein-1, and macrophage content of visceral adipose tissue were reduced in Lepr(db/db),Psgl-1(-/-) compared with Lepr(db/db),Psgl-1(+/+) mice. Reduced leukocyte-endothelial interactions and macrophage content of visceral adipose tissue due to Psgl-1 deficiency was also observed in a diet-induced obese mouse model. Psgl-1(-/-) mice were resistant to the endothelial effects of exogenous IL-1beta, suggesting that defective cytokine signaling contributes to the effect of Psgl-1 deficiency on leukocyte-endothelial interactions. Mice deficient in the IL-1 receptor also had reduced levels of circulating P-selectin, similar to those observed in Psgl-1(-/-) mice. Deficiency of Psgl-1 is associated with reduced IL-1 receptor-mediated adhesive properties of the endothelium and is protective against visceral fat inflammation in obese mice.