Figure 5. Trafficking of leukocytes to interstitial space.

A. Leukocyte rolling, adhesion and transmigration. The original three steps are shown in bold: rolling, which is mediated by selectins, activation, which is mediated by chemokines, and arrest, which is mediated by integrins. Progress has been made in defining additional steps: capture (or tethering), slow rolling, adhesion strengthening and spreading, intravascular crawling, and paracellular and transcellular transmigration. Key molecules involved in each step are indicated in boxes. ESAM, endothelial cell-selective adhesion molecule; ICAM1, intercellular adhesion molecule 1; JAM, junctional adhesion molecule; LFA1, lymphocyte function-associated antigen 1 (also known as _L2-integrin); MAC1, macrophage antigen 1; MADCAM1, mucosal vascular addressin cell-adhesion molecule 1; PSGL1, P-selectin glycoprotein ligand 1; PECAM1, platelet/endothelial-cell adhesion molecule 1; PI3K, phosphoinositide 3-kinase; VCAM1, vascular cell-adhesion molecule 1; VLA4, very late antigen 4 (also known as ₄₁-integrin). B. Migration of leukocytes through vascular walls. This process involves penetrating the endothelial-cell barrier and its associated basement membrane and the pericyte sheath. (a) Extension of leukocyte membrane protrusions into the endothelial-cell body and endothelial-cell junctions is triggered by ligation of intercellular adhesion molecule 1 (ICAM1) by MAC1 (macrophage antigen 1). Ligation of ICAM1 is associated with increased intracellular Ca²⁺ and activation of p38 mitogen-activated protein kinase (MAPK) and RAS homologue (RHO) GTPase, which may collectively activate myosin light-chain kinase leading to enhanced endothelial-cell contraction and hence opening of inter-endothelial contacts. These events may promote leukocyte migration through endothelial junctions (paracellular route), although leukocyte migration can also occur through the body of the endothelium (transcellular route). Transmigration through the endothelium can also induce cell-surface expression of members of the ₁-integrin family and proteases on neutrophils and other leukocytes that may facilitate the onwards movement of the leukocyte through the vessel wall. (b) Paracellular migration involves the release of endothelial-expressed vascular endothelial cadherin (VE-cadherin) and is facilitated by intracellular membrane compartments containing a pool of platelet/endothelial-cell adhesion molecule 1 (PECAM1) and possibly other endothelial-cell junctional molecules, such as junctional adhesion molecule A (JAM-A). Other molecules involved in paracellular transmigration are endothelial cell-selective adhesion molecule (ESAM), ICAM2 and CD99. (c) Transcellular migration occurs in 'thin' parts of the endothelium, and therefore there is less distance for a leukocyte to migrate. ICAM1 ligation leads to translocation of ICAM1 to actin- and caveolae-rich regions. ICAM1-containing caveolae link together forming vesiculo-vacuolar organelles (VVOs) that form an intracellular channel through which a leukocyte can migrate. Ezrin, radixin and moesin (ERM) proteins could act as linkers between ICAM1 and cytoskeletal proteins (such as actin and vimentin), causing their localization around the channel, thereby providing structural support for the cell under these conditions. (d) Migration through the endothelial basement membrane and pericyte sheath can occur through gaps between adjacent pericytes and regions of low protein deposition within the extracellular matrix. This response can be facilitated by ₆₁-integrin and possibly proteases, such as matrix metalloproteinases (MMPs) and neutrophil elastase (NE). Figure and legend are reprinted with permission from [217].