Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 15, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn193
p55 TNF Receptor in bone marrow-derived cells promotes atherosclerosis development in LDL receptor knock-out mice
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1 Department of Molecular Genetics and Cardiovascular Research Institute Maastricht, Maastricht University, 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. University of Maastricht, Cardiovascular Research Institute Maastricht, Department of Molecular Genetics, Universiteitssingel 50, UNS 50/11, 6229ER, Maastricht, The Netherlands. Tel. +31 433881746; Fax. +31 433884574. E-mail: s.xanthoulea{at}gen.unimaas.nl
Aims: Tumor 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 and in atherosclerotic lesion development.
Methods: Irradiated low-density lipoprotein (LDL) receptor knock-out mice were reconstituted with either p55 TNFR knock-out or control hematopoietic stem cells to generate chimeras deficient for p55 TNFR, or wild-type, specifically in bone marrow-derived cells, including macrophages.
Results: 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 to controls, before and after high fat feeding.
Conclusions: 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 like MCP-1.
KEYWORDS atherosclerosis; macrophages; inflammation; leukocytes; cytokines
Time for primary review: 25 days
current address: Department of Pathology and Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands