P-selectin glycoprotein ligand-1 regulates adhesive properties of the endothelium and leukocyte trafficking into adipose tissue

Abstract

Rationale: 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. Objective: 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. Methods and Results: 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 (Leprdb/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 Leprdb/db,Psgl- 1-/-compared with Leprdb/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-1β, 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. Conclusions: 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. © 2010 American Heart Association, Inc.