Inflammatory Blues Turns Velvet Skin Into Rawhide

Abstract

The directed homing of leukocytes is crucial during immune surveillance or inflammation and is accomplished by a complex cooperation of signaling and adhesion molecules.1,2 Its pathophysiologic relevance is exemplified by various inflammatory diseases such as atherosclerosis.3 At present, the course of leukocyte trafficking is well established through the classical multistep cascade of initial tethering and rolling of leukocytes over vascular endothelium, followed by firm adhesion and their subsequent spreading and transendothelial migration.1,2 Leukocyte rolling is mediated by a subgroup of C-type lectins; E-, L-, and P-selectin, through shear-resistant binding to particular cell-surface carbohydrates. E- and L-selectin are expressed on activated endothelial cells and most leukocytes, respectively, while P-selectin is stored in the secretory compartments of platelets and endothelial cells to become rapidly upregulated on cell activation. The best characterized ligand for selectins is P-selectin glycoprotein ligand-1 (PSGL-1),4 a heavily posttranslationally modified homodimeric transmembrane glycoprotein. PSGL-1 contains functionally essential sialylated and fucosylated carbohydrate moieties, known as sialyl Lewis X (sLex) groups, and is expressed on blood cells such as neutrophils, monocytes, and platelets.5 The importance of PSGL-1 for cell recruitment is highlighted by studies using transgenic mice deficient in PSGL-1, which revealed a crucial contribution to P-selectin–dependent rolling on inflamed endothelium, indicating a function of PSGL-1 in early inflammatory responses.6 Presented by endothelium-bound leukocytes, PSGL-1 supports the initial L-selectin–dependent tethering of blood-borne leukocytes to the already adherent leukocytes at the inflamed vessel wall followed by E-selectin-mediated rolling on the endothelium.7 Besides supporting leukocyte–endothelium interactions, PSGL-1 promotes the P-selectin–dependent initial tethering of platelets to monocytes8,9 followed by more stable interactions through integrins expressed on both platelets and monocytes. In addition, the interaction between PSGL-1 and P-selectin also plays an essential role in the delivery …