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Del-1, an Endogenous LeukocyteEndothelial Adhesion Inhibitor, Limits Inflammatory Cell Recruitment
Eun Young Choi,1* Emmanouil Chavakis,2* Marcus A. Czabanka,3† Harald F. Langer,1† Line Fraemohs,4 Matina Economopoulou,5 Ramendra K. Kundu,6 Alessia Orlandi,2 Ying Yi Zheng,1 DaRue A. Prieto,7 Christie M. Ballantyne,8 Stephanie L. Constant,9William C. Aird,10 Thalia Papayannopoulou,11 Carl G. Gahmberg,12 Mark C. Udey,13 Peter Vajkoczy,3 Thomas Quertermous,6 Stefanie Dimmeler,2 Christian Weber,4 Triantafyllos Chavakis1‡ Leukocyte recruitment to sites of infection or inflammation requires multiple adhesive events. Although numerous players promoting leukocyte-endothelial interactions have been characterized, functionally importantendogenous inhibitors of leukocyte adhesion have not been identified. Here we describe the endothelially derived secreted molecule Del-1 (developmental endothelial locus–1) as an anti-adhesive factor that interferes with the integrin LFA-1–dependent leukocyteendothelial adhesion. Endothelial Del-1 deficiency increased LFA-1–dependent leukocyte adhesion in vitro and in vivo. Del-1−/− mice displayedsignificantly higher neutrophil accumulation in lipopolysaccharide-induced lung inflammation in vivo, which was reversed in Del-1/LFA-1 double-deficient mice. Thus, Del-1 is an endogenous inhibitor of inflammatory cell recruitment and could provide a basis for targeting leukocyte-endothelial interactions in disease. eukocyte extravasation is integral to the response to infection or injury and toinflammation and autoimmunity. Leukocyte recruitment comprises a well-coordinated cascade of adhesive events, including selectin-mediated rolling, firm adhesion of leukocytes to endothelial cells, and their subsequent transendothelial migration. The interaction between LFA-1 (also known as aLb2 and CD11a/CD18) and endothelial intercellular adhesion molecule–1 (ICAM-1) is crucial during firm endothelialadhesion of leukocytes
angiogenesis (10–12). We sought to determine whether endothelially derived Del-1 participates in leukocyte-endothelial interactions. Del-1 mRNA was observed predominantly in the brain and lung, with no expression in the liver, spleen, or whole blood (Fig. 1A and fig. S1A). Del-1 was expressed in wild-type (WT) but not in Del-1−/− murine lung endothelial cells (Fig. 1B)(9). In lung tissues, Del-1 was present in blood vessels (fig. S1B). To determine whether Del-1 participates in leukocyte recruitment interactions, we studied the adhesion of primary neutrophils to immobi1 Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA. 2Molecular Cardiology, Department of InternalMedicine III, J. W. Goethe University, Frankfurt, Germany. 3Department of Neurosurgery, Charite Universitätsmedizin, Berlin, Germany. 4Institute for Molecular Cardiovascular Research, RWTH University Hospital, Aachen, Germany. 5Laboratory of Cellular Oncology, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA. 6 Division of Cardiovascular Medicine, Stanford University School of Medicine, PaloAlto, CA, USA. 7Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, NCI, Frederick, MD, USA. 8Baylor College of Medicine and Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA. 9Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC, USA. 10Molecular and Vascular Medicine,Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 11Department of Medicine/Hematology, University of Washington, Seattle, WA, USA. 12Division of Biochemistry, Faculty of Biosciences, University of Helsinki, Finland. 13Dermatology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
(1–5). Whereas numerous adhesion receptors promoting inflammatory...
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