Molecular Mechanisms of Endothelial Leukocyte Association

Abstract

Attachment of leukocytes to the blood vessel wall initiates leukocyte extravasation. This enables leukocytes to migrate to and accumulate at sites of tissue injury or infection where they execute host-defense mechanisms. A series of vascular cell adhesion molecules on leukocytes and on endothelial cells mediate and control leukocyte attachment to the endothelium in a stepwise process (Springer, 1994) (Figure 1). Members of the selectin family of adhesion molecules mediate the initial tethering and rolling of leukocytes on the activated endothelium through interactions with carbohydrate-bearing ligands. This allows leukocytes to slow down and to interact with other molecules on the endothelial cell surface which induce activation of the leukocytes. Such activating agents can be the phospholipid platelet activating factor PAF or chemokines which are presented by endothelial proteoglycans. They can bind to various receptors which contain seven membrane spanning regions. Signal cascades which are triggered by these receptors lead to the activation of integrins on the leukocyte cell surface which bind to members of the immunoglobulin (Ig) super family on the endothelial cell surface. Such pairs of cell adhesion molecules are involved in a second adhesion step which is more firm than the selectin mediated initial tethering of leukocytes to the endothelium. Adhesion via activated integrins is a prerequisite for the active migration of leukocytes on the endothelial cell surface and finally through the layer of endothelial cells. Very little is known about this last step of the active transmigration process. It is still a matter of debate, whether leukocytes transmigrate through the junctions between adjacent endothelial cells or directly through a single endothelial cell. This review will mainly focus on the selectin mediated initiation of leukocyte tethering to the endothelium.