How Endothelial Cells Regulate Transmigration of Leukocytes in the Inflammatory Response

Leukocytes attach to vascular endothelial cells at the site of inflammation via a series of intercellular adhesive interactions. In a separate step in leukocyte extravasation, transendothelial migration is regulated by molecules that play no role in the preceding steps of tethering, rolling, adhesion, and locomotion. Transendothelial migration itself can be dissected into a series of distinct interactions regulated sequentially by molecules concentrated at the endothelial cell border; these include platelet/endothelial cell adhesion molecule, poliovirus receptor (CD155), and CD99. These molecules are components of the lateral border recycling compartment (LBRC), a perijunctional network of interconnected tubulovesicular membrane that traffics to surround the leukocyte as it passes across the endothelial cell. This targeted recycling of LBRC requires kinesin to move the membrane along microtubules, and interfering with LBRC trafficking blocks transmigration of neutrophils, monocytes, and lymphocytes. The LBRC is also recruited to mediate transcellular migration when that occurs. Movement of the LBRC is coordinated with events on the luminal surface, such as clustering of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 under the migrating leukocyte, as well as movement of vascular endothelial cadherin and its associated catenins out of the junction at the site of transendothelial migration. How these events are coordinated is not known, but their regulation shares common signaling pathways that may serve to connect these steps.