- Role of nuclear receptor Nur77 during inflammation
C.J.M. de Vries
V. de Waard
- Award date
- 19 February 2015
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Nuclear Receptors play key roles in cell differentiation and development, homeostasis and in many diseases such as diabetes, cancer, cardiovascular disease, reproductive abnormalities and obesity; and are therefore major targets for drug discovery. Nur77 is, like most nuclear receptors, a transcription factor and thus directly regulates the expression of a specific set of genes. In this thesis we studied the nuclear receptor Nur77 in the inflammatory diseases atherosclerosis, inflammatory bowel disease (IBD) and peritonitis.
We investigated the effect of Nur77-deficiency in primary bone marrow-derived mouse macrophages and found a more pro-inflammatory phenotype. To study the role of Nur77 in acute inflammation, Nur77-deficient mice were injected with Escherichia coli bacteria establishing a peritoneal sepsis. At the onset of peritonitis Nur77 increases bacterial influx into the organs due to enhanced vascular permeability, resulting in increased tissue damage. Atherosclerosis may be considered a chronic, lipid-driven inflammation of the vessel wall. Macrophages play a crucial role in initiation and progression of this disease. We show that bone marrow-specific Nur77-deficiency aggravates atherosclerosis in dedicated mouse models. IBD represents a group of chronic inflammatory intestinal conditions. Within the last era, it has become clear that next to immunological and environmental factors, also genetic factors play an important role in the pathogenesis of IBD. In experimental colitis our data support a protective function for Nur77 in IBD.
Taken together we conclude that in acute infection Nur77 aggravates the disease, whereas this nuclear receptor has a protective function in chronic inflammation in atherosclerosis and inflammatory bowel disease.
- Research conducted at: Universiteit van Amsterdam
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