Leukocytes constantly patrol the vascular system in order to react promptly to infections when and where it is necessary. To fulfil this task, the cells have to enter secondary lymphoid organs and to emigrate into inflamed tissues, which requires them to cross the barrier of endothelial cells that line blood vessels. Transendothelial migration into inflamed tissues is preceded by a sequence of leukocyte–endothelial cell interactions, generally referred to as the ‘multistep adhesion cascade’ (Fig. 1). The cascade is initiated by inflammatory signals that cause local activation of vascular endothelium. Activated endothelial cells express Eand P-selectin molecules that capture leukocytes from the bloodstream and mediate rolling of the cells by binding to glycoconjugate ligands on the leukocyte surface. Homing to secondary lymphoid organs is initiated by interactions of L-selectin (expressed by leukocytes) with glycoconjugates on high endothelial venules. Rolling allows the leukocytes to perceive and accumulate signals that are mediated by the binding of endothelial-bound chemokines to their leukocyte receptors. These signals lead to leukocyte activation, resulting in a transfer of leukocyte integrins into a high affinity conformation. The integrins now allow the leukocytes to adhere firmly to the endothelium by interactions with intercellular adhesion molecule-1 and ⁄or vascular cell adhesion molecule-1. The leukocytes then migrate to sites where they can cross the endothelial layer, using either a paracellular pathway through intercellular junctions, or a transcellular pathway through the endothelial cell body. This minireview series comprises five reviews that cover important aspects of leukocyte–endothelial cell interactions (indicated in Fig. 1). In the first review, Markus Sperandio considers in vivo results on selectinmediated leukocyte rolling. He describes the requirements for rolling interactions and reviews the current knowledge of the functional relevance of the various known selectin ligands. This review focuses in particular on the glycosyland sulfotransferases that are required for the post-translational modification of selectin ligands and for which a series of knockout animals is available. The second review, by Sviatlana Yakubenia & Martin K. Wild, deals with leukocyte adhesion deficiency II, a human congenital disease in which hypofucosylation prevents selectin binding and leukocyte capture ⁄ rolling, thus inducing an immunodeficiency. The review describes recent advances on the genetic defects in patients with leukocyte adhesion deficiency II. It also focuses on open questions concerning the molecular basis of the therapy for leukocyte adhesion deficiency II and the mechanisms of the developmental defects that accompany the immunodeficiency in this disease. The third review, by Bjorn Petri & Gabriele Bixel, discusses current knowledge on the interaction of cell adhesion molecules during leukocyte transendothelial migration. In contrast to leukocyte rolling and firm adhesion, leukocyte diapedesis, and the routes taken by migrating leukocytes, are less well understood. The article focuses on cell adhesion molecules that are known to participate in the process of leukocyte extravasation, including cell surface molecules such as platelet ⁄ endothelial cell adhesion molecule-1, members of the junctional adhesion molecule family and CD99. Junctional cell adhesion molecules are believed to be important for paracellular transmigration, with leukocytes squeezing through between adjacent endothelial cells. In addition, leukocytes can cross the endothelium via an alternative pathway whereby they migrate through the body of an endothelial cell. To date, not much is known about the molecular players involved in the latter pathway. However, endothelial components, such as intermediate filaments and caveolae, seem to be important for this process. The fourth review, by Peter Hordijk, summarizes recent progress made towards an understanding of the signaling pathways that are induced in endothelial cells during leukocyte extravasation. A series of studies clearly shows that endothelial cells play an active role in this process, allowing leukocytes to cross the vascular endothelium via the paracellular or the transcellular pathway. Adhesion of leukocytes to the luminal surface of the vascular endothelium induces the formation of a docking structure that is associated with the clustering of adhesion and signaling molecules. This local concentration of cell adhesion molecules, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, is believed to be required for the initiation of endothelial signaling. Both intracellular calcium and the actin cytoskeleton, but also small GTPases, reactive oxygen species and protein kinases, are involved in these signaling events. doi: 10.1111/j.1742-4658.2006.05436.x
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