Mechanisms and consequences of neutrophil interaction with the endothelium

Abstract

Leukocyte recruitment into inflamed tissue proceeds in a cascade-like fashion. The first contact of neutrophils with the endothelium is mediated by selectins and their counterreceptors, followed by rolling of neutrophils along the endothelial wall of postcapillary venules and integrin-mediated arrest. While rolling, neutrophils collect different inflammatory signals that can activate several pathways. In addition to activation of neutrophils by ligation of G-protein-coupled receptors with chemokines and other chemoattractants, integrins and selectin ligands are also able to signal into the cell, where they initiate neutrophil extravasation, promote cytoskeletal rearrangement, and ultimately induce superoxide production and degranulation. These signaling pathways may be targeted by therapeutic interventions to inhibit specific functions of neutrophils without affecting others. This Review is focused on the signaling events during the interaction of neutrophils with the endothelium.

Figure 1

Activation of signaling pathways during the contact of neutrophils with the endothelium. E-selectin binding to PSGL-1 leads, through Syk, to partial LFA-1 activation (black curved arrow) that mediates rolling on ICAM-1 (shown as a dimer). L-selectin engagement may activate, through ERM proteins, the neutrophil and induce integrin activation. Activation of GPCRs leads to dissociation of the G protein in a Gα-subunit and a Gβγ-complex. The Gα-subunit inhibits some, but not all, adenylyl cyclase isoforms. The Gβγ-complex interacts directly with PI3Kγ, PLCβ, and P-Rex-1. The activation of these enzymes can induce degranulation, O₂⁻ production, migration, phagocytosis, integrin clustering, and full activation of the integrin (gray curved arrow). LFA-1 interaction with its counterreceptor triggers outside-in signaling and further activates the neutrophil. Arrows indicate signaling pathways, but interactions may be indirect. α_iβγ, G-protein subunits; AC, adenylyl cyclase; [Ca²⁺]_i, intracellular calcium; GPCR, G-protein-coupled receptor; IP₃, inositol triphosphate; PRex, PtdIns(3,4,5)P3-dependent Rac exchanger.