ANTIINFLDEL

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

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 Obiettivo del progetto (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'

Introduzione (Teaser)

Understanding the process of inflammation is central for treating or preventing inflammatory conditions. By focusing on a secreted molecule that blocks inflammation, European researchers provided a novel therapeutic angle.

Descrizione progetto (Article)

During inflammation, leukocytes get recruited to the injured site following a cascade of events that involve activation and migration from the vessels within the endothelium. Several adhesion receptors, including integrins, such as lymphocyte function-associated antigen 1 (LFA-1), promote interactions between leukocytes and the vascular endothelium. Although many adhesion receptors are known to promote leukocyte recruitment, very little information exists about endogenous inhibitors of the cascade.

Scientists on the EU-funded project 'The anti-inflammatory actions of developmental endothelial locus-1 (Del-1)' (ANTIINFLDEL) identified the endothelial-derived secreted molecule Del-1 as an endogenous anti-inflammatory agent. This molecule antagonises LFA-1-dependent leukocyte adhesion and recruitment at the site of inflammation. Also, mice lacking Del-1 display a pro-inflammatory phenotype with higher leukocyte recruitment.

The scope of ANTIINFLDEL was to delineate the role of Del-1 in inflammation of neuronal organs, such as the retina of the eye. Researchers found that Del-1 is expressed in immune-privileged sites, including the brain and retina, and that expression was abundant in neuronal cells. In addition, induction of inflammation in mice correlated with a reduction in Del-1 levels.

Taken together, these observations underscore the homeostatic importance of Del-1 in immune-privileged sites. They also suggest that long-term Del-1 could be exploited therapeutically to reduce the extent of inflammation.