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Recent findings show that DEL1 (developmental endothelial locus 1; also known as EDIL3) - a glycoprotein secreted by endothelial cells - can inhibit the process that leukocytes use to bind to the vascular endothelium and enter inflamed tissues.
A glycoprotein that is produced by endothelial cells has been identified as a new endogenous inhibitor of the leukocyte adhesion cascade. A study in Science shows that DEL1 (developmental endothelial locus 1; also known as EDIL3) can inhibit the process by which leukocytes bind to the vascular endothelium to enter inflamed tissues.
Messenger RNA encoding DEL1 was found mainly in the brain and lungs, and was shown to be expressed by endothelial cells in lung blood vessels. In an in vitro assay, mouse primary neutrophils bound to immobilized DEL1, and this adhesion could be blocked by a monoclonal antibody specific for CD11a. This indicates that the interaction with DEL1 is mediated by the integrin lymphocyte function-associated antigen 1 (LFA1, composed of CD11a and CD18 subunits); indeed, LFA1-deficient neutrophils had decreased adhesion to DEL1.
In contrast to this DEL1–LFA1-mediated adhesion, neutrophils and monocytes were found to adhere to DEL1-deficient endothelial cells at significantly higher levels than to wild-type cells. This increased adherence was abolished for LFA1-deficient leukocytes or by the addition of a monoclonal antibody specific for LFA1. Consistent with this, as assessed by intravital microscopy, leukocyte adhesion to postcapillary venules was higher in DEL1-deficient mice than in wild-type mice. To clarify the role of DEL1 in adhesion, the authors directly compared the ability of DEL1 and the LFA1 ligand intercellular adhesion molecule 1 (ICAM1) to promote adhesion under different physiological flow conditions. ICAM1 promoted firm adhesion of neutrophils at both high and low shear rates, whereas DEL1 promoted weak adhesion only at the low shear rate, which indicates that DEL1 is not a physiologically relevant adhesion molecule. Also, both soluble DEL1 and DEL1 co-immobilized with ICAM1 significantly inhibited the adhesion of neutrophils to ICAM1, which indicates that DEL1 interferes with LFA1-dependent adhesion to ICAM1.
The ability of DEL1 to interfere with leukocyte recruitment by this mechanism was tested in vivo in a model of lipopolysaccharide (LPS)-induced lung inflammation. DEL1-deficient mice had a greater accumulation of neutrophils in the broncho-alveolar lavage than wild-type mice. Mice that were deficient in both DEL1 and LFA1 had a similar decrease in neutrophil accumulation to LFA1-deficient mice, which shows that leukocyte recruitment in DEL1-deficient mice requires LFA1.
These results indicate that DEL1 has an anti-inflammatory function by restricting leukocyte recruitment to inflamed tissues. In line with this, the level of mRNA encoding DEL1 was significantly decreased in lung tissue after LPS administration to allow for an efficient inflammatory response. Therapeutic manipulation of the level of DEL1 could therefore hold promise for enhancing or inhibiting leukocyte recruitment to diseased tissues.