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Science 322 (5904): 1101-1104

Copyright © 2008 by the American Association for the Advancement of Science

Del-1, an Endogenous Leukocyte-Endothelial Adhesion Inhibitor, Limits Inflammatory Cell Recruitment

Eun Young Choi,1* Emmanouil Chavakis,2* Marcus A. Czabanka,3{dagger} Harald F. Langer,1{dagger} 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,9 William 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{ddagger}

Abstract: Leukocyte recruitment to sites of infection or inflammation requires multiple adhesive events. Although numerous players promoting leukocyte-endothelial interactions have been characterized, functionally important endogenous 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 leukocyte-endothelial adhesion. Endothelial Del-1 deficiency increased LFA-1–dependent leukocyte adhesion in vitro and in vivo. Del-1–/– mice displayed significantly 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.

1 Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.
2 Molecular Cardiology, Department of Internal Medicine III, J. W. Goethe University, Frankfurt, Germany.
3 Department of Neurosurgery, Charite Universitätsmedizin, Berlin, Germany.
4 Institute for Molecular Cardiovascular Research, RWTH University Hospital, Aachen, Germany.
5 Laboratory of Cellular Oncology, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
6 Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.
7 Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, NCI, Frederick, MD, USA.
8 Baylor College of Medicine and Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA.
9 Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC, USA.
10 Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
11 Department of Medicine/Hematology, University of Washington, Seattle, WA, USA.
12 Division of Biochemistry, Faculty of Biosciences, University of Helsinki, Finland.
13 Dermatology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.

* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: chavakist{at}mail.nih.gov

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