Mechanisms of leukocyte transendothelial migration

Abstract

Neither the innate nor adaptive immune system "responds" unless leukocytes cross blood vessels. This process occurs through diapedesis, in which the leukocyte moves in an ameboid fashion through tightly apposed endothelial borders and, in some cases, through the endothelial cell itself. This review focuses on the active role of the endothelial cell in diapedesis. Several mechanisms play a critical role in transendothelial migration, including signals derived from clustering of apically disposed intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, disruption or loosening of adherens junctions, and targeted recycling of platelet/endothelial cell adhesion molecule and other molecules from the recently described lateral border recycling compartment. Surprisingly, many of the same molecules and mechanisms that regulate paracellular migration also control transcellular migration. A hypothesis that integrates the various known mechanisms of transmigration is proposed.

Figure 1

Schematic view of the movement of the lateral border recycling compartment (LBRC) during paracellular transmigration. (a) Constitutive recycling of the LBRC is ongoing as the leukocyte locomotes toward the intercellular border. (b) Upon reaching the apical side of the endothelial border, leukocyte platelet/endothelial cell adhesion molecule (PECAM) engages endothelial cell PECAM, which is enriched in plasma membrane at the cell borders (and in the LBRC). (c) In cases of PECAM-dependent transmigration, leukocyte PECAM–endothelial cell PECAM interaction triggers a signal (lightning bolt) that redirects recycling of the LBRC to the site of leukocyte engagement. In cases of PECAM-independent transmigration, some other interaction triggers this signal. (d) Membrane from the interconnected vesicles of the LBRC moves to surround the leukocyte. (e) Recruitment of the LBRC continues as the leukocyte crosses the endothelial cell border. Endothelial cell thickness is exaggerated to allow depiction of the LBRC and various signaling molecules. In reality, the endothelial cell is ≤0.5 µm thick, and the leukocyte is ~7–10 µm in diameter. Modified from Reference with permission.

Figure 2

A unified schematic view of paracellular transendothelial migration. (a) Clustering of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) through engagement of their leukocyte integrin counterreceptors (αβ in diagram) initiates activation of src, Rho A, and Rac-1, as well as increased cytosolic free calcium ion. Phosphorylation of cortactin by src stimulates F-actin rearrangements in the cortical cytoplasm, which facilitates more ICAM-1 clustering. (b) These signals lead to activation of myosin light-chain kinase (MLCK), inactivation of PP1c, and phosphorylation of vascular endothelial cell–specific cadherin (VE-cadherin), inducing release of the associated catenins. (c) Leukocyte platelet/endothelial cell adhesion molecule (PECAM) engagement of endothelial cell PECAM, and/or other leukocyte/endothelial cell interactions at the apical surface of the endothelial border, activates kinesin molecular motors in the endothelial cell and stimulates targeted trafficking of LBRC membrane to the vicinity of the leukocyte. (d) Targeted trafficking of LBRC membrane continues as the leukocyte moves into the border between endothelial cells, which is now enlarged by the contribution of membrane from the LBRC. This process continues until transmigration is complete. Abbreviations: CaM, calmodulin; ROCK, Rho kinase; ROS, reactive oxygen species; circled P, phosphorylated state. Reprinted from Reference with permission.

Figure 3

Schematic view of the movement of the lateral border recycling compartment (LBRC) during paracellular transmigration. (a) The signal that recruits targeted recycling to the vicinity of the leukocyte (lightning bolt) is transmitted while the leukocyte is on the apical surface of the endothelial cell. (b) This process causes targeting of the LBRC membrane along cortical microtubules toward the leukocyte. (c) A single fusion event may be sufficient to allow the entire interconnected LBRC to come into contact with the leukocyte. (d–f) As the leukocyte passes through the endothelial cell, additional LBRC membrane is recruited to surround the leukocyte. The transmigration pore is thus essentially a parajunctional junction lined by molecules the leukocyte needs to interact with [e.g., platelet/endothelial cell adhesion molecule (PECAM), CD99, junctional adhesion molecule (JAM)-A] and lacking those it needs to bypass [e.g., vascular endothelial (VE)-cadherin and associated proteins]. (g) At the basal surface, a second fusion event may be necessary to allow the leukocyte to complete its migration across the endothelial cell. (h) The leukocyte is now in communication with the subendothelial basement membrane and completes diapedesis as if it had migrated paracellularly.