Mechanisms of Transendothelial Migration of Leukocytes

Abstract

Abstract-A great deal of progress has been made recently in understanding the molecules and mechanisms that regulate transendothelial migration of leukocytes, or diapedesis, a critical step in the inflammatory response. This review focuses mainly on the active role of the endothelial cell in this process as it occurs at endothelial cell borders. It discusses some of the many molecules that have been reported to play a role in transendothelial migration and asks why so many molecules seem to be involved. The concept is emerging that diapedesis itself can be dissected into sequential steps controlled by specific molecule(s) at the endothelial cell border. Several mechanisms have been shown to 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. A hypothesis that integrates the various known mechanisms is proposed. Key Words: transendothelial migration Ⅲ inflammation Ⅲ leukocyte Ⅲ endothelial cell Ⅲ transmigration T he inflammatory response is the stereotyped reaction of the body to tissue damage of any kind. It involves rapidly and transiently delivering preformed soluble elements in the blood to the site of injury followed by a more prolonged delivery of leukocytes. Because leukocytes cannot swim, they are recruited locally at the site of inflammation in a series of adhesive steps that allow them to attach to the vessel wall, locomote along the wall to the endothelial borders, traverse the endothelium and the subendothelial basement membrane, and migrate through the interstitial tissue. 1,2 Transendothelial migration (TEM) or diapedesis is arguably the point of no return in the inflammatory response. The preceding steps of leukocyte rolling, activation, adhesion, and locomotion are all reversible, and most leukocytes that initiate contact with the postcapillary venule at the site of inflammation reenter the circulation. However, once the leukocyte commits to diapedesis, it does not go back, at least not as the same cell type. 3 Most TEM takes place at endothelial borders. Recently, there has been a flurry of interest in TEM through the endothelial cell body (transcellular migration). Although this clearly can occur in vitro 4 and in vivo, 5 in the interests of space, this review focuses on transendothelial migration and specifically TEM at cell borders. Unfortunately, because of space limitations, a great many excellent publications on this subject cannot be cited. Molecules Regulating TransmigrationA number of molecules have been implicated in transmigration because genetic deletion or antibody blockade of these molecules impairs diapedesis. All of these molecules belong to a recognized family of adhesion molecules, are expressed on endothelial cells, and are enriched at cell borde...

Ezrin-Radixin-Moesin-binding Phosphoprotein 50 (EBP50) and Nuclear Factor-κB (NF-κB)

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TLR3-dependent immune regulatory functions of human mesangial cells

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Endothelial Outgrowth Cells: Function and Performance in Vascular Grafts

“…53 When activated by injury or inflammatory cytokines, ECs facilitate inflammation by (1) releasing chemotactic factors to attract circulating leukocytes, (2) expressing selectins to allow leukocyte rolling adhesion along the vessel wall, (3) loosening intercellular junctions with adjacent ECs, and (4) expressing integrin ligands to permit leukocyte diapedesis into the tissue. Although this review will highlight the role of only a few endothelial inflammatory markers, more thorough reviews of leukocyte adhesion, 54 transmigration, 55 and atherogenesis 56 have been previously published. Circulating leukocytes can be transiently bound by E-and P-selectins on cytokine-stimulated ECs to facilitate rolling adhesion along the vessel wall.…”