Cardiovascular Research Advance Access originally published online on July 15, 2008
Cardiovascular Research 2008 80(2):309-318; doi:10.1093/cvr/cvn193
p55 Tumour necrosis factor receptor in bone marrow-derived cells promotes atherosclerosis development in low-density lipoprotein receptor knock-out mice
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1 Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, UNS 50/11, 6229ER Maastricht, The Netherlands
2 Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
3 Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
* Corresponding author. Tel: +31 43 388 1746; fax: +31 43 388 4574. E-mail address: s.xanthoulea{at}gen.unimaas.nl
Aims: Tumour necrosis factor (TNF) is a pivotal pro-inflammatory cytokine with a clear pathogenic role in many chronic inflammatory diseases, and p55 TNF receptor (TNFR) mediates the majority of TNF responses. The aim of the current study was to investigate the role of p55 TNFR expression in bone marrow-derived cells, in atherosclerotic lesion development.
Methods and results: Irradiated low-density lipoprotein receptor knock-out mice were reconstituted with either p55 TNFR knock-out or control haematopoietic stem cells to generate chimeras deficient or wild-type for p55 TNFR specifically in bone marrow-derived cells, including macrophages. Upon high fat feeding, p55 TNFR knock-out transplanted mice developed smaller atherosclerotic lesions. These lesions were characterized by the presence of smaller foam cells and a reduced macrophage foam cell area. They did not differ in other compositional characteristics as determined by quantification of inflammatory T-cell and neutrophil influx, apoptotic and necrotic cell death, and collagen content. In vitro studies confirmed a significant defect in modified lipoprotein endocytosis by p55 TNFR knock-out macrophages due to reduced scavenger receptor class A expression. Interestingly, plasma cytokine/chemokine profile analysis indicated that monocyte chemoattractant protein-1 (MCP-1) levels, a major chemokine involved in atherogenesis, were consistently and significantly lower in p55 TNFR knock-out transplanted mice compared with controls, before and after high fat feeding.
Conclusion: p55 TNFR expression in bone marrow-derived cells contributes to the development of atherosclerosis by enhancing lesional foam cell formation and by promoting the expression of pro-atherosclerotic chemokines such as MCP-1.
KEYWORDS Atherosclerosis; Macrophages; Inflammation; Leukocytes; Cytokines
Time for primary review: 25 days
Present address. Department of Pathology and Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands.