Selectins: initiators of leucocyte adhesion and signalling at the vascular wall

Abstract

The selectins are transmembrane, Ca(2+)-dependent lectins that mediate leucocyte rolling on vascular surfaces, the first adhesive step during inflammation and immune surveillance. Leucocytes express L-selectin, activated platelets express P-selectin, and activated endothelial cells express E- and P-selectin. Rolling involves force-regulated, rapidly reversible interactions of selectins with a limited number of glycosylated cell surface ligands. Rolling permits leucocytes to interact with immobilized chemokines that convert β2 integrins to high-affinity conformations, which mediate arrest, post-arrest adhesion strengthening, and transendothelial migration. However, rolling leucocytes also transduce signals through selectin ligands, the focus of this review. These signals include serial activation of kinases and recruitment of adaptors that convert integrins to intermediate-affinity conformations, which decrease rolling velocities. In vitro, selectin signalling enables myeloid cells to respond to suboptimal levels of chemokines and other agonists. This cooperative signalling triggers effector responses such as degranulation, superoxide production, chemokine synthesis, and release of procoagulant/proinflammatory microparticles. In vivo, selectin-mediated adhesion and signalling likely contributes to atherosclerosis, arterial and deep vein thrombosis, ischaemia-reperfusion injury, and other cardiovascular diseases.

Keywords: Cell adhesion; Inflammation; Integrin; Neutrophil; Selectin.

Figure 1

Multistep leucocyte adhesion cascade. Endothelial selectins initiate tethering and rolling of leucocytes, including neutrophils as depicted here. Signals from engaged selectins and chemokines activate β2 integrins that mediate slow rolling and arrest. Integrins also direct spreading, intraluminal crawling, and migration between or through endothelial cells into perivascular tissues. Inset: Adherent neutrophils polarize to form a leading edge (lamellipodium) and a trailing edge (uropod). The selectin ligand PSGL-1 redistributes to the uropod and captures activated platelets by interacting with P-selectin. Platelet–neutrophil interactions transduce signals that facilitate intraluminal crawling.

Figure 2

Integrin activation in rolling neutrophils. Left, signals transmitted through selectin ligands, e.g. PSGL-1 or CD44, convert integrin αLβ2 to an extended conformation that retains a closed headpiece with low affinity for ICAM-1. This conformation decreases rolling velocities. Right, signals transmitted through chemokine receptors, e.g. CXCL1, convert αLβ2 to an extended conformation that has an open headpiece with high affinity for ICAM-1. This conformation causes arrest. Both conformations require recruitment of talin to β2 tails. The extended, high-affinity conformation also requires kindlin and actomyosin-dependent tension.

Figure 3

Selectin signalling cascade in neutrophils. Engagement of PSGL-1 or CD44 triggers serial activation of kinases and recruitment of adaptors, resulting in talin-dependent activation of integrin αLβ2 that mediates slow rolling on ICAM-1.