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

Abstract

Leukocyte recruitment to sites of infection or inflammation requires multiple adhesive events. While numerous players promoting leukocyte-endothelial interactions have been characterized, functionally important endogenous inhibitors of leukocyte adhesion have not been identified. Here, we describe the endothelial-derived secreted molecule, developmental endothelial locus-1 (Del-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 LPS-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.Leukocyte 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 & This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS. †To whom correspondence should be addressed chavakist@mail.nih.gov. * EYC and EC contributed equally # MAC and HL contributed equally NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript their subsequent transendothelial migration. The interaction between LFA-1 (αLβ2, CD11a/ CD18) and endothelial ICAM-1 is crucial during firm endothelial adhesion of leukocytes (1-5). Whereas numerous adhesion receptors promoting inflammatory cell recruitment have been identified, very little information exists about endogenous inhibitors of the leukocyte adhesion cascade (1-7). Developmental endothelial locus-1 (Del-1) is a glycoprotein that is secreted by endothelial cells and can associate with the endothelial cell surface and the extracellular matrix (8-10). Del-1 is regulated upon hypoxia or vascular injury and has been implicated in vascular remodelling during angiogenesis (10-12). Here, we sought to determine whether endothelial-derived Del-1 participates in leukocyte-endothelial interactions. RT-PCR analysis revealed Del-1 mRNA predominantly in the brain and lung, with no expression in liver, spleen, or whole blood (Fig. 1A and fig. S1A). Del-1 was expressed in WT but not in Del-1-/-murine lung endothelial cells (Fig. 1B, 9). Immunohistochemistry of lung tissues demonstrated the presence of Del-1 in vessels, as observed by co-staining with the endothelial marker PECAM-1 ( fig. S1B).To determine whether Del-1 participates in leukocyte recruitmen...

Integrin Regulation during Leukocyte Recruitment

“…The 52-kDa glycoprotein Del-1 has been shown to interfere with the binding of the activated integrin to its ligand: as a potential LFA-1 ligand, endothelial-derived Del-1 features a higher affinity compared with ICAM-1 and thus functions as a competitive antagonist, effectively hampering leukocyte adhesion (74). Accordingly, mice lacking endothelial Del-1 displayed increased neutrophil infiltration in a model of LPS-induced pulmonary infiltration (74). GDF-15.…”

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

“…Cell adhesion was monitored by phase contrast on a Zeiss Axiovert 40 CFL microscope and Zeiss A-Plan 10 Â /0.25 Ph1 lens, using a Hamamatsu ORCA-03G digital camera and Cellix VenaFlux software. Computerized image analysis was performed by DucoCell analysis software (Cellix, Dublin), where adherent eosinophils were quantified on each single image [41,61]. …”

Age-associated changes in innate immunity and their impacts on inflammatory disease.

“…In contrast to PTX3, however, Del-1 is produced by the tissue rather than the inflammatory cell itself [52,73]. Specifically, Del-1 is secreted by endothelial cells and may associate with the endothelial cell surface and the extracellular matrix [43,62].…”

“…and Oel-r'--LFA-r'-mice was previously described [52]. In this study, the Oel-r'- standardized for measurements in millimeters.…”

“…Defines neutrophils [51] ICAM-1 Plays a critical role in the neutrophil recruitment [48,49] LFA-1 (CD11a/ldgal) Plays a critical role in the neutrophil recruitment [48,49] Inhibits LFA-1-ICAM-1 interactions and limits neutrophil migration to sites Del-1 of infection/inflammation [52] CD62E Increases LFA-1 affinity to ICAM-1 [53] KC (CXCL 1) Involved in neutrophil chemotaxis [54,55] Chemokine produced by neutrophils; induces Th17 migration to sites of [56,57] by antagonizing the interaction between ICAM-1 and LFA-1 ( Figure 4) [52]. It also has been shown that Del-1 induced engulfment of apoptotic cells [72].…”