Role of Netrin-1 during Resolvin mediated resolution of inflammation

• Applicant: Professorin Dr. Valbona Mirakaj
• Subject Area: Anaesthesiology
• Term: from 2010 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 193499911

During acute inflammation immune competent cells extravasate from the intravascular space and infiltrate the site of inflammation. This is mediated through positive guidance cues such as chemokines. Recent work has identified the neuronal guidance molecule netrin-1 to control leukocyte migration and to hold anti-inflammatory potential. This acute inflammatory process is subsequently limited by the initiation of physiological resolution of inflammation. Promotion of resolution comprises suppression of pro-inflammatory gene expression, a reduction of leukocyte activation followed by inflammatory cell clearance through apoptosis and phagocytosis. These points are stimulated by a family of pro-resolving mediators termed resolvins. We have strong evidence that netrin-1 is involved in the resolvin system. We found that Resolvin D1 (RvD1) and aspirin triggered AT-Resolvin (AT-RvD1) result in a robust induction of netrin-1 mRNA expression and netrin-1 promoter activity. Using a model of hind limb ischemia-reperfusion and a model of mechanical lung injury the interplay between RvD1/ AT-RvD1 and endogenous netrin-1 expression could be confirmed. Therefore, we will investigate the link between the neuronal guidance protein netrin-1 and the resolvin system. Major aim is to define the functional impact of this interaction on the resolution of an inflammatory process. This work will be performed in the laboratory of Professor Serhan at the Harvard Medical School, who is a world renowned expert in the field of resolution of inflammation. Initially, we will investigate the alteration of endogenous resolvin levels in animals with endogenous repression of netrin-1 (Ntn1+/-). We will then highlight the timeline of the resolution of inflammation using resolution index and a differential of cells that are crucial for the phagocytosis of inflammatory cells, such as macrophages, within the inflammatory compartment. Furthermore, we will then determine the influence of RvD1 and AT-RvD1 on endogenous netrin-1 expression and its functional impact on the resolution of inflammation in Ntn1+/- and controls. This would give the applicant the opportunity to pursue a possible interaction between two previously as independent regarded systems of inflammatory control. In addition this would enable the applicant to increase her methodological portfolio and deepen her understanding of netrin-1.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Charles N. Serhan