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Leukocyte transmigration is mediated by endothelial cell (EC) junctional molecules, but the associated mechanisms remain unclear. Here we investigate how intercellular adhesion molecule-2 (ICAM-2), junctional adhesion molecule-A (JAM-A), and platelet endothelial cell adhesion molecule (PECAM-1) mediate neutrophil transmigration in a stimulus-dependent manner (eg, as induced by interleukin-1β [IL-1β] but not tumor necrosis factor-α [TNF-α]), and demonstrate their ability to act in sequence. Using a cell-transfer technique, transmigration responses of wild-type and TNF-α p55/p75 receptor-deficient leukocytes (TNFR−/−) through mouse cremasteric venules were quantified by fluorescence intravital microscopy. Whereas wild-type leukocytes showed a normal transmigration response to TNF-α in ICAM-2−/−, JAM-A−/−, and PECAM-1−/− recipient mice, TNFR−/− leukocytes exhibited a reduced transmigration response. Hence, when the ability of TNF-α to directly stimulate neutrophils is blocked, TNF-α–induced neutrophil transmigration is rendered dependent on ICAM-2, JAM-A, and PECAM-1, suggesting that the stimulus-dependent role of these molecules is governed by the target cell being activated. Furthermore, analysis of the site of arrest of neutrophils in inflamed tissues from ICAM-2−/−, JAM-A−/−, and PECAM-1−/− mice demonstrated that these molecules act sequentially to mediate transmigration. Collectively, the findings provide novel insights into the mechanisms of action of key molecules implicated in leukocyte transmigration.

The cytoplasmic domain of cadherins and the associated catenins link the cytoskeleton with signal transduction pathways. To study the signaling function of non-junctional VE-cadherin, which can form during the loss VE-cadherin homotypic adhesion, wild type VE-cadherin or VE-cadherin cytoplasmic domain (DeltaEXD) was expressed in sub-confluent endothelial cells. We observed that Cdc42 was activated in transfected cells and that these cells also developed Cdc42-dependent >70-microm-long plasma membrane protrusions. The formation of these structures required actin polymerization, and they developed specifically in endothelial cells as compared with epithelial cells. Expression of the VE-cadherin cytoplasmic domain lacking the beta-catenin binding site also induced Cdc42 activation; thus, its activation cannot be ascribed to beta-catenin binding. However, these cells were not able to form the protrusions. These results suggest that the cytoplasmic domain of non-junctional VE-cadherin can serve as a scaffold involved in Cdc42 activation at the endothelial plasma membrane. beta-Catenin and the associated alpha-catenin may serve as support sites for actin polymerization, leading to formation of long plasma membrane protrusions. Thus, non-junctional VE-cadherin actively participates in inside-out signaling at the plasma membrane, leading to the development of endothelial membrane protrusions. J Biol Chem

The immune system consists of a complex collection of leukocytes and dendritic cells that surveys most tissues in the body for the appearance of foreign antigens. For an efficient immune response, the interaction and co-localization of antigen-presenting cells, costimulatory helper cells and effector cells are crucial parameters. Therefore, the migration routes of antigen-presenting cells and potential antigen-specific lymphocytes merge in secondary lymphoid organs in order to increase the likelihood and speed of a lymphocyte finding its cognate antigen. Additionally, antigen-primed effector cells are directed to the tissue where they are most likely to encounter their cognate antigen. This highly organized and efficient antigen encounter is based on a continuous recirculation of antigen-specific lymphocytes between blood, peripheral tissue, and secondary lymphoid organs. Moreover, the efficacy of the immune system is further increased by the ability of different lymphocyte subsets to recirculate only through distinct tissues. The scope of this review is to outline the concept and mechanisms of lymphocyte homing and recirculation and to discuss the significance for the immune defense. Current models in leukocyte homing and recirculation and the underlying molecular functions of implicated cell adhesion molecules, chemokines, and chemokine receptors are discussed.

Proof that plants possess homologs of animal adhesion proteins is lacking. In this paper we describe the generation of monoclonal antibodies that interfere with cell-cell contacts in the 4-cell embryo of the multicellular alga Volvox carteri, resulting in a hole between the cells. The number of following cell divisions is reduced and the cell division pattern is altered drastically. Antibodies given at a later stage of embryogenesis specifically inhibit inversion of the embryo, a morphogenetic movement that turns the embryo inside out. Immunofluorescence microscopy localizes the antigen (Algal-CAM) at cell contact sites of the developing embryo. Algal-CAM is a protein with a three-domain structure: an N-terminal extensin-like domain characteristic for plant cell walls and two repeats with homology to fasciclin I, a cell adhesion molecule involved in the neuronal development of Drosophila. Alternatively spliced variants of Algal-CAM mRNA were detected that are produced under developmental control. Thus, Algal-CAM is the first plant homolog of animal adhesion proteins.