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 β2 integrin LFA-1 and promote slow rolling, whereas ESL-1 induces signals that activate the β2 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.

Figure 1

Topography and signaling pathways triggered by selectin ligands in neutrophils. (A) Topography of selectin ligands on neutrophils. Based on biochemical and electron microscopic evidence, PSGL-1 is thought to be concentrated in lipid rafts on the tips of microvilli. Electron microscopy places (some of) ESL-1 on microvilli, but not necessarily the tips, whereas CD44 is concentrated in the valleys between microvilli. LFA-1 and Mac-1 are thought to be mostly on the cell body. (B) Signaling pathways of selectin ligands in neutrophils. Engagement of PSGL-1 by P-selectin or E-selectin or engagement of CD44 by E-selectin induces activation of the SFKs Fgr, Hck, and Lyn.^, The activated SFKs phosphorylate the ITAM domains of DAP-12 and FcRγ, enabling them to recruit spleen tyrosine kinase Syk. Knocking out Fgr or knocking out both Hck and Lyn blocks this signaling pathway.^, Direct physical association between PSGL-1, CD44, and the SFKs has not been demonstrated. Syk activity is needed to activate Bruton tyrosine kinase (Btk), which leads to phospholipase C-γ2 (PLCγ2) activation, providing diacylglycerol (DAG) for the activation of CalDAG-GEFI, an exchange factor for the small G protein Rap-1. Rap-1 drives LFA-1 extension through other signaling intermediates (not shown). Engagement of ESL-1 by E-selectin has been shown to activate Mac-1, but the signaling pathway is unknown.