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      PECAM-1 (CD31) Homophilic Interaction Up-Regulates α 6β 1 on Transmigrated Neutrophils In Vivo and Plays a Functional Role in the Ability of α 6 Integrins to Mediate Leukocyte Migration through the Perivascular Basement Membrane

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          Abstract

          Platelet-endothelial cell adhesion molecule (PECAM)-1 has been implicated in leukocyte migration through the perivascular basement membrane (PBM) though the mechanisms involved are unclear. The present results demonstrate that the ability of α 6 integrins to mediate neutrophil migration through the PBM is PECAM-1 dependent, a response associated with PECAM-1–mediated increased expression of α 6β 1 on transmigrating neutrophils in vivo. An anti-α 6 integrins mAb (GoH3) inhibited (78%, P < 0.001) neutrophil migration through interleukin (IL)-1β–stimulated cremasteric venules, primarily at the level of the PBM, as analyzed by intravital and electron microscopy. In PECAM-1–deficient mice (KO), a reduced level of neutrophil transmigration elicited by IL-1β (4-h reaction) was observed in both the cremaster muscle (55% inhibition, P < 0.05) and in the peritoneum (57% inhibition, P < 0.01) but GoH3 had no additional inhibitory effect on these responses. FACS ® analysis of neutrophils demonstrated increased expression of α 6β 1 on transmigrated peritoneal neutrophils, as compared with blood neutrophils, in wild-type but not KO mice even though neutrophils from both strains of mice exhibited comparable levels of intracellular expression of α 6 as observed by immunofluorescent staining and confocal microscopy. Furthermore, mice deficient in either leukocyte or endothelial cell PECAM-1, as developed by bone marrow transplantation, demonstrated a similar level of reduced neutrophil transmigration and expression of α 6β 1 on transmigrated neutrophils as that detected in KO mice.

          The results demonstrate a role for PECAM-1 homophilic interaction in neutrophil transmigration and increased expression of α 6β 1 on the cell surface of transmigrated neutrophils in vivo, a response that could contribute to the mechanism of PECAM-1–mediated neutrophil migration through the PBM.

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          Most cited references 43

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          Leukocyte-endothelial adhesion molecules.

           J Harlan,  T. Carlos (1994)
          In the 9 years since the last review on leukocyte and endothelial interactions was published in this journal many of the critical structures involved in leukocyte adherence to and migration across endothelium have been elucidated. With the advent of cell and molecular biology approaches, investigations have progressed from the early descriptions by intravital microscopy and histology, to functional and immunologic characterization of adhesion molecules, and now to the development of genetically deficient animals and the first phase I trial of "anti-adhesion" therapy in humans. The molecular cloning and definition of the adhesive functions of the leukocyte integrins, endothelial members of the Ig gene superfamily, and the selectins has already provided sufficient information to construct an operative paradigm of the molecular basis of leukocyte emigration. The regulation of these adhesion molecules by chemoattractants, cytokines, or chemokines, and the interrelationships of adhesion pathways need to be examined in vitro and, particularly, in vivo. Additional studies are required to dissect the contribution of the individual adhesion molecules to leukocyte emigration in various models of inflammation or immune reaction. Certainly, new adhesion structures will be identified, and the current paradigm of leukocyte emigration will be refined. The promise of new insights into the biology and pathology of the inflammatory and immune response, and the potential for new therapies for a wide variety of diseases assures that this will continue to be an exciting area of investigation.
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            Macromolecular organization of basement membranes.

             Rupert Timpl (1996)
            A considerable variety of basement membrane components, including in particular more than ten laminin isoforms and their novel alpha chains (alpha3, alpha4 and alpha5), has been characterized in recent studies. The functional properties of these components are increasingly being analyzed by recombinant technologies and by structural studies at atomic resolution, techniques which led to the elucidation of the nidogen-binding epitope on the laminin gamma1 chain. Novel insights into functions of basement membrane components have been obtained from gene-targeting experiments and studies of mutated genes identified in inherited disorders.
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              CD99 plays a major role in the migration of monocytes through endothelial junctions.

              CD99 is a heavily O-glycosylated 32-kD type I transmembrane protein that is expressed on most hematopoietic cells. We show here that CD99 is expressed on endothelial cells and is concentrated at the borders between confluent cells. We found that a monoclonal antibody to CD99, hec2, selectively inhibited diapedesis of monocytes across endothelial cells by >90%. Diapedesis involved the homophilic interaction of CD99 on monocytes with CD99 on endothelial junctions. CD99 functioned distally to the point at which platelet-endothelial cell adhesion molecule 1 (PECAM-1, also known as CD31), another adhesion molecule involved in transmigration, played its critical role. Confocal microscopy showed that anti-PECAM-1 arrested leukocytes on the apical surface of endothelium, whereas blocking CD99 arrested monocytes at a point where they were partially through the junction. Therefore, diapedesis, the forward migration of leukocytes through endothelial junctions, is regulated sequentially by two distinct molecules, PECAM-1 and CD99.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                4 November 2002
                : 196
                : 9
                : 1201-1212
                Affiliations
                [1 ]Cardiovascular Medicine Unit, National Heart & Lung Institute, Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 ONN, United Kingdom
                [2 ]National Heart and Lung Institute, Electron Microscopy Unit, Imperial College, Royal Brompton Hospital, London SW3 6NP, United Kingdom
                Author notes

                Address correspondence to Dr. Sussan Nourshargh, Cardiovascular Medicine Unit, National Heart and Lung Institute, Faculty of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. Phone: 44-20-8383-1621; Fax: 44-20-8383-1640; E-mail: s.nourshargh@ 123456ic.ac.uk

                Article
                20020324
                10.1084/jem.20020324
                2194111
                12417630
                Copyright © 2002, The Rockefeller University Press
                Categories
                Article

                Medicine

                intravital microcopy, inflammation, laminin, integrins, adhesion molecules

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