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      The Functional Paradox of CD43 in Leukocyte Recruitment: A Study Using CD43-deficient Mice

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          Abstract

          Although there is considerable evidence implicating a role for CD43 (leukosialin) in leukocyte cell–cell interactions, its precise function remains uncertain. Using CD43-deficient mice (CD43 −/−) and intravital microscopy to directly visualize leukocyte interactions in vivo, we investigated the role of CD43 in leukocyte–endothelial cell interactions within the cremasteric microcirculation under flow conditions. Our studies demonstrated significantly enhanced leukocyte rolling and adhesion after chemotactic stimuli in CD43 −/− mice compared with wild type mice. Using an in vitro flow chamber, we established that the enhanced rolling interactions of CD43 −/− leukocytes, primarily neutrophils, were also observed using immobilized E-selectin as a substrate, suggesting that passive processes related to steric hindrance or charge repulsion were likely mechanisms. Despite increased adhesion and rolling interactions by CD43 −/− leukocytes, we uncovered a previously unrecognized impairment of CD43 −/− leukocytes to infiltrate tissues. Oyster glycogen–induced neutrophil and monocyte infiltration into the peritoneum was significantly reduced in CD43 −/− mice. In response to platelet activating factor, CD43 −/− leukocytes were impaired in their ability to emigrate out of the vasculature. These results suggest that leukocyte CD43 has a dual function in leukocyte–endothelial interactions. In addition to its role as a passive nonspecific functional barrier, CD43 also facilitates emigration of leukocytes into tissues.

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          Most cited references33

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          Lymphocyte homing and homeostasis.

          The integration and control of systemic immune responses depends on the regulated trafficking of lymphocytes. This lymphocyte "homing" process disperses the immunologic repertoire, directs lymphocyte subsets to the specialized microenvironments that control their differentiation and regulate their survival, and targets immune effector cells to sites of antigenic or microbial invasion. Recent advances reveal that the exquisite specificity of lymphocyte homing is determined by combinatorial "decision processes" involving multistep sequential engagement of adhesion and signaling receptors. These homing-related interactions are seamlessly integrated into the overall interaction of the lymphocyte with its environment and participate directly in the control of lymphocyte function, life-span, and population dynamics. In this article a review of the molecular basis of lymphocyte homing is presented, and mechanisms by which homing physiology regulated the homeostasis of immunologic resources are proposed.
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            Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1).

            Lymphocyte function-associated antigen 1 (LFA-1) is a leukocyte cell surface glycoprotein that promotes intercellular adhesion in immunological and inflammatory reactions. It is an alpha beta complex that is structurally related to receptors for extracellular matrix components, and thus belongs to the integrin family. ICAM-1 (intercellular adhesion molecule-1) is a distinct cell surface glycoprotein. Its broad distribution, regulated expression in inflammation, and involvement in LFA-1-dependent cell-cell adhesion have suggested that ICAM-1 may be a ligand for LFA-1. We have purified ICAM-1 and incorporated it into artificial supported lipid membranes. LFA-1+ but not LFA-1- cells bound to ICAM-1 in the artificial membranes, and the binding could be specifically inhibited by anti-ICAM-1 treatment of the membranes or by anti-LFA-1 treatment of the cells. The cell binding to ICAM-1 required metabolic energy production, an intact cytoskeleton, and the presence of Mg2+ and was temperature dependent, characteristics of LFA-1- and ICAM-1-dependent cell-cell adhesion.
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              P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin

              Neutrophils roll on P-selectin expressed by activated platelets or endothelial cells under the shear stresses in the microcirculation. P- selectin glycoprotein ligand-1 (PSGL-1) is a high affinity ligand for P- selectin on myeloid cells. However, it has not been demonstrated that PSGL-1 contributes to the rolling of neutrophils on P-selectin. We developed two IgG mAbs, PL1 and PL2, that appear to recognize protein- dependent epitopes on human PSGL-1. The mAbs bound to PSGL-1 on all leukocytes as well as on heterologous cells transfected with PSGL-1 cDNA. PL1, but not PL2, blocked binding of 125-I-PSGL-1 to immobilized P-selectin, binding of fluid-phase P-selectin to myeloid and lymphoid leukocytes, adhesion of neutrophils to immobilized P-selectin under static conditions, and rolling of neutrophils on P-selectin-expressing CHO cells under a range of shear stresses. PSGL-1 was localized to microvilli on neutrophils, a topography that may facilitate its adhesive function. These data indicate that (a) PSGL-1 accounts for the high affinity binding sites for P-selectin on leukocytes, and (b) PSGL- 1 must interact with P-selectin in order for neutrophils to roll on P- selectin at physiological shear stresses.
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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
                7 December 1998
                : 188
                : 11
                : 2181-2186
                Affiliations
                From the [* ]Immunology Research Group, the []Department of Medicine, and the [§ ]Department of Physiology and Biophysics, University of Calgary, Calgary,  Alberta, Canada T2N 4N1
                Author notes

                Address correspondence to Paul Kubes, Health Science Center, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1. Phone: 403-220-8558; Fax: 403-283-1267; E-mail: pkubes@ 123456acs.ucalgary.ca ; and reprint requests to Richard C. Woodman, Health Science Center, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1. Phone: 403-220-7658; Fax: 403-283-1267; E-mail: woodman@ 123456acs.ucalgary.ca

                Article
                2212397
                9841931
                cb9cb143-5b6e-42de-ba42-b98202e364d8
                Copyright @ 1998
                History
                : 2 April 1998
                : 5 October 1998
                Categories
                Brief Definitive Reports

                Medicine
                cd43,leukocytes,recruitment,antiadhesive,emigration
                Medicine
                cd43, leukocytes, recruitment, antiadhesive, emigration

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