MINIREVIEW SERIES Leukocyte–endothelial cell interactions Martin K. Wild and M. Gabriele Bixel 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 bar- rier 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 adhe- sion cascade’ (Fig. 1). The cascade is initiated by inflam- matory signals that cause local activation of vascular endothelium. Activated endothelial cells express E- and 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 para- cellular 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 selectin- mediated leukocyte rolling. He describes the require- ments for rolling interactions and reviews the current knowledge of the functional relevance of the various known selectin ligands. This review focuses in partic- ular on the glycosyl- and sulfotransferases that are required for the post-translational modification of selectin ligands and for which a series of knockout ani- mals 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 des- cribes 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 accom- pany the immunodeficiency in this disease. The third review, by Bjo ¨ rn 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 extra- vasation, 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 leuko- cytes 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 compo- nents, 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 vascu- lar endothelium via the paracellular or the transcellular pathway. Adhesion of leukocytes to the luminal sur- face of the vascular endothelium induces the formation of a docking structure that is associated with the clus- tering 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 FEBS Journal 273 (2006) 4375–4376 ª 2006 The Authors Journal compilation ª 2006 FEBS 4375 The final review (by Nicole Kaneider, Andrew Leger and Athan Kuliopulos) of our series addresses thera- peutic strategies that aim to interfere with leukocyte– endothelial cell interactions in order to limit the pro- gression of inflammatory diseases, such as arterioscler- osis, rheumatic arthritis and multiple sclerosis. Although recruitment of leukocytes to the site of injury or infection is a physiological response, cell infil- tration into healthy areas, or overzealous leukocyte accumulation, can have adverse consequences for the surrounding tissue and contribute to a wide variety of inflammatory diseases. This article summarizes current clinical therapeutic strategies and anti-inflammatory drugs that interfere at various stages of the multistep adhesion cascade. The five contributing minireviews reflect the recent progress in our understanding of leukocyte–endothelial interactions during the past few years. We are confid- ent that this knowledge will help to open new avenues of immunomodulation for therapeutic purposes. Fig. 1. The multistep leukocyte adhesion cascade and topics covered by this minireview series. The figure depicts the cascade of leuko- cyte–endothelial cell interactions that leads to leukocyte emigration from blood vessels into tissues. The endothelial layer covering the lumenal side of vessels is shown in orange with some of the important surface molecules expressed upon activation. The topics of the five reviews in this series are indicated by arrows. LAD II, leukocyte adhesion deficiency II. M. Gabriele Bixel is a senior scientist at the Max Planck Institute of Molecular Biomedicine, Mu ¨ nster, and the Insti- tute of Cell Biology, ZMBE, of the Mu ¨ nster University. She received her PhD in biochemistry in 1998 from the Uni- versity of Tu ¨ bingen. During her postdoctoral training at the Free University of Berlin she investigated the modulation of neuroreceptor function by noncompetitive inhibitors. Since 2001, her research has focused on the molecular mechanisms involved in leukocyte recruitment from the circulating blood into the tissue during inflammation. Martin K. Wild is a senior scientist at the Max Planck Institute for Molecular Biomedicine, Mu ¨ nster, and the Insti- tute of Cell Biology, ZMBE, of Mu ¨ nster University. He completed his PhD at the German Cancer Research Cen- ter in Heidelberg before he moved to Oxford, UK, where he undertook postdoctoral research at the Sir William Dunn School of Pathology. His current research focuses on human leukocyte adhesion deficiencies, immune interventions and dendritic cell migration. Leukocyte–endothelial cell interactions M. K. Wild and M. G. Bixel 4376 FEBS Journal 273 (2006) 4375–4376 ª 2006 The Authors Journal compilation ª 2006 FEBS . layer, using either a para- cellular pathway through intercellular junctions, or a transcellular pathway through the endothelial cell body. This minireview. adhesion deficiencies, immune interventions and dendritic cell migration. Leukocyte–endothelial cell interactions M. K. Wild and M. G. Bixel 4376 FEBS Journal