Inflamaçao

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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,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‡ 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 leukocyteendothelial 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. eukocyte extravasation is integral to the response to infection or injury and to inflammation 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 endothelial