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Contenuto archiviato il 2024-06-18

The anti-inflammatory actions of Developmental Endothelial Locus-1 (Del-1)

Final Report Summary - ANTIINFLDEL (The anti-inflammatory actions of Developmental Endothelial Locus-1 (Del-1))

A major process in inflammation and inflammatory diseases is leukocyte extravasation and recruitment to the inflamed or injured tissue. Several adhesion receptors, e.g. of the integrin family, such as LFA-1, promote the interactions between leukocytes and the vascular endothelium including the firm leukocyte-endothelial adhesion and thereby leukocyte recruitment. We have recently identified the endothelial-derived secreted molecule, Developmental endothelial locus-1 (Del-1), as an endogenous anti-inflammatory agent that antagonizes LFA-1-dependent leukocyte recruitment. Here, we studied Del-1 expression and function in hypoxia-induced inflammation and in the course of inflammatory processes affecting neuronal organs, such as the retina of the eye or other components of the central nervous system. By exposing mice to ambient hypoxia, we have found a downregulation of Del-1 expression in the lung. More strikingly, we found that this endogenous anti-inflammatory factor is highly expressed in immune-privileged tissues, such as the brain and the retina. Specifically, by performing histology analysis and tracking endogenous Del-1 expression via staining for beta-galactosidase in Del-1-deficient mice that contain a LacZ knock-in, which serves as a reporter for Del-1 expression, we observed that while Del-1 was found expectedly in the retina vessels, a large part of Del-1 expression in the retina was found in neuronal cells; we could further characterize Del-1 expression in different retinal neuronal subpopulations. In particular, we found that different neuronal subpopulations in the retina, including amacrine, horizontal and bipolar cells expressed Del-1. Moreover, Del-1 expression in the retina was reduced upon LPS (endotoxin) administration, in line with our previous findings that Del-1 expression is reduced by inflammatory processes. Furthermore, Del-1 in the central nervous system (brain) was predominantly present in neuronal cells (besides the endothelium), as assessed by the approach described above (beta-galactosidase staining). Taken together, Del-1 is a homeostatic factor of the immune-privileged retina, where it is present mostly in neuronal cells and its expression is downregulated by inflammation.