ANTIINFLDEL · The anti-inflammatory actions of Developmental Endothelial Locus-1 (Del-1)
FP7 — People (Marie Curie Actions)
- Duration
- 2010-09-01 → 2014-08-31
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-IRG
Lines connect the coordinator with its partners.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
Leukocyte recruitment is an important component of inflammatory and autoimmune disorders and consists of selectin-mediated rolling, the chemokine-induced activation of leukocytes, the integrin-dependent firm adhesion and the subsequent transendothelial migration. LFA-1 is an important leukocyte integrin mediating adhesion by binding to its endothelial counter-receptors ICAM-1 and -2. Whereas many adhesion receptors are known to promote leukocyte recruitment, very little information exists about endogenous inhibitors of the cascade. The lab of the applicant has recently identified the endothelial-derived secreted molecule Developmental Endothelial Locus-1 (Del-1, Edil3) as a potent endogenous inhibitor of the leukocyte adhesion cascade. Del-1 acted as an inhibitor of LFA-1-dependent leukocyte adhesion to the endothelium. Consistently, Del-1-/- mice displayed a pro-inflammatory phenotype with higher leukocyte recruitment in vivo.Recently, we found that Del-1 expression is abundant in the immunoprivileged eye. In the first aim of the present project we plan to study the expression and functional contribution of Del-1 in models of eye inflammation. These studies may identify Del-1 as novel therapeutic approach in eye inflammation.In addition, previous reports have demonstrated that Del-1 is elevated by tissue ischemia or hypoxia. Relative tissue hypoxia is a hallmark of acute inflammation. The mechanisms regulating the hypoxia-related anti-inflammatory response are not well understood. In the second aim of this project we will study whether Del-1 acts to regulate the hypoxia-related anti-inflammatory response. The pro-inflammatory effects of hypoxia in mice can be tested in models of ambient hypoxic exposure (e.g. 8% oxygen for 4-8 h) that induce increased permeability of endothelial and epithelial barriers e.g. lung and intestine, as well as enhanced recruitment of inflammatory cells.In summary the present proposal will focus on characterizing further the fun
Original text from CORDIS.
Participants
- TECHNISCHE UNIVERSITAET DRESDEN · DresdenCoordinatorGermany
Links
Data: CORDIS, © European Union