Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow

Abstract

Reversible interactions of glycoconjugates on leukocytes with P-and E-selectin on endothelial cells mediate tethering and rolling of leukocytes in inflamed vascular beds, the first step in their recruitment to sites of injury. Although selectin ligands on hematopoietic precursors have been identified, here we review evidence that PSGL-1, CD44, and ESL-1 on mature leukocytes are physiologic glycoprotein ligands for endothelial selectins. Each ligand has specialized adhesive functions during tethering and rolling. Furthermore, PSGL-1 and CD44 induce signals that activate the ␤2 integrin LFA-1 and promote slow rolling, whereas ESL-1 induces signals that activate the ␤2 integrin Mac-1 in adherent neutrophils. We also review evidence for glycolipids, CD43, L-selectin, and other glycoconjugates as potential physiologic ligands for endothelial selectins on neutrophils or lymphocytes. Although the physiologic characterization of these ligands has been obtained in mice, we also note reported similarities and differences with human selectin ligands. (Blood. 2011;118(26):6743-6751) IntroductionThe selectins mediate adhesion of hematopoietic cells to vascular surfaces and to each other. 1 These interactions are important for host defense, hematopoiesis, immune cell surveillance, hemostasis, and inflammation. Each of the 3 selectins is a type I transmembrane protein with an N-terminal C-type lectin domain, an epidermal growth factor-like domain, a series of consensus repeats, a transmembrane domain, and a short cytoplasmic tail. L-selectin is constitutively expressed on most leukocytes. P-selectin is rapidly mobilized from secretory granules to the plasma membranes of platelets and endothelial cells on stimulation. E-selectin expression on endothelial cells is regulated at the transcriptional level by inflammatory mediators, such as tumor necrosis factor-␣.The rolling cell adhesion mediated by selectins is a dynamic process that requires rapid formation and breakage of bonds under flow. 2 Rolling enables cells to receive signals that activate integrins, another class of adhesion receptors, which cause the cells to roll slower and to arrest. 3 Here we discuss how leukocytes, particularly neutrophils, interact with endothelial selectins during inflammation. We review evidence that surprisingly few neutrophil glycoproteins are physiologic selectin ligands, defined by their ability to mediate rolling adhesion. Rolling can be studied with flow chambers in vitro or ex vivo and in transparent tissues or by epifluorescence in vivo.The selectins are Ca 2ϩ -dependent lectins. The minimal glycan determinant for selectin binding is sialyl Lewis x (sLe x ; NeuAc␣2,3Gal␤1,4[Fuc␣1,3]GlcNAc␤1-R). 1 The fucose moiety of sLe x expressed on selectin ligands forms critical interactions with the Ca 2ϩ -coordination site on the lectin domain of selectins. 2 Leukocytes from mice lacking the 2 ␣1,3-fucosyltransferases that add fucose to form sLe x on hematopoietic cells cannot roll on Pand E-selectin. 4 Because sLe x can potentially cap N-and O-gl...

Two new susceptibility loci 1q24.2 and 11p11.2 confer risk to severe acne

“…L-selectin is expressed on the surface of most circulating leukocytes, facilitating leukocyte migration into secondary lymphoid organs and inflammation sites. P-and E-selectin, expressed on inflamed endothelium 22 , are likewise responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining 23 . Analysis of the gene expression profiles revealed that the mRNA expression of SELL was upregulated in acne lesions 24 .…”

Silencing α1,3-Fucosyltransferases in Human Leukocytes Reveals a Role for FUT9 Enzyme during E-selectin-mediated Cell Adhesion

“…Although much of our knowledge of glycoTs regulating selectin-ligand synthesis is derived from mice, these animals differ from humans particularly with respect to E-selectin and its ligands (1,6). In this regard, although E-selectin binding to mouse granulocytes is completely lost upon pronase digestion, it is only partially reduced in human cells (7,8).…”

“…Together, the rolling experiments with L-E cells and stimulated HUVEC confirm a more significant role for FUT9 and FUT7, as opposed to FUT4, during HL-60 rolling on E-selectin. The apparent importance of FUT9 in human leukocyte adhesion is not entirely unexpected because it is well recognized that the E-selectin ligands in human leukocytes differ from those in the mouse (1,5). In particular, E-selectin ligands on mouse but not human neutrophils are pronase-sensitive (7,8).…”

“…Three members of the selectin family of adhesion molecules, E-(CD62E), P-(CD62P), and L-selectin (CD62L), regulate the capture of leukocytes from flowing blood to sites of inflammation under hydrodynamic/fluid shear conditions (1). Such rapid molecular bond formation at high on-rates is enabled by unique protein-carbohydrate interactions between the selectins and their sialofucosylated ligands that are expressed on the leukocytes (2).…”

Severe Impairment of Leukocyte Recruitment in ppGalNAcT-1–Deficient Mice

“…Transfection of fucosyltransferase VII into different cell lines conferred the ability to bind to E-selectin in flow chamber experiments (39,40), indicating that the glycoprotein requirements for E-selectin binding may be more relaxed than for Pselectin. The three glycoproteins PSGL-1, CD44, and ESL-1 on murine leukocytes are the most physiologically relevant E-selectin ligands (41). Elimination of PSGL-1 impairs E-selectin-mediated tethering in vitro and in vivo (42).…”