Project R-2334

The role of liver x receptors in the macrophage response after myelin phagocytosis (Research)

Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system (CNS) in which macrophages play a pivotal role. Initially, macrophages where thought to be only detrimental in MS, as they phagocytose myelin and secrete toxic mediators. However, recent evidence suggests that macrophages can also have anti-inflammatory effects and have the capacity to induce repair. Nonetheless, underlying mechanisms inducing a protective phenotype in macrophages remain to be clarified. Liver X receptors (LXRs) are ligand dependent transcription factors that regulate the expression of genes involved in cholesterol metabolism. In addition, LXRs have been described to repress the expression of certain inflammatory genes in macrophages. Since myelin contains cholesterol, which is the natural ligand for LXRs, these receptors may play a role in the induction of a protective phenotype in macrophages. We hypothesize that LXRs are activated after myelin phagocytosis and induce a protective, anti-inflammatory phenotype in macrophages. The goal of this study is to unravel the role of LXRs in the macrophage response after myelin phagocytosis. The activation of LXR response genes, after myelin phagocytosis, will be studied in mouse peritoneal macrophages by real-time PCR. The functionality of this activation will be investigated by cholesterol efflux assays. Next, macrophage production of inflammatory mediators after myelin phagocytosis will be investigated with ELISA, immunocytochemistry, NO-assays and DHR-assays. Finally, the in vitro data will be validated by using the experimental autoimmune encephalomyelitis (EAE) and cuprizone mouse model. This study will lead to an increased knowledge about the role of LXRs in the induction of a protective phenotype in macrophages after myelin phagocytosis. Furthermore, the acquired knowledge can lead to the development of more efficient therapies for MS.

01 October 2009 - 30 September 2013