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Grandoch M.,Heinrich Heine University Düsseldorf | Grandoch M.,Cardiovascular Research Institute Dusseldorf CARID | Feldmann K.,Heinrich Heine University Düsseldorf | Feldmann K.,Cardiovascular Research Institute Dusseldorf CARID | And 23 more authors.
Circulation Research | Year: 2015

Rationale: Lymphotoxin β receptor (LTbR) regulates immune cell trafficking and communication in inflammatory diseases. However, the role of LTbR in atherosclerosis is still unclear. Objective: The aim of this study was to elucidate the role of LTbR in atherosclerosis. Methods and Results: After 15 weeks of feeding a Western-type diet, mice double-deficient in apolipoprotein E and LTbR (apoE-/-/LTbR-/-) exhibited lower aortic plaque burden than did apoE-/- littermates. Macrophage content at the aortic root and in the aorta was reduced, as determined by immunohistochemistry and flow cytometry. In line with a decrease in plaque inflammation, chemokine (C-C motif) ligand 5 (Ccl5) and other chemokines were transcriptionally downregulated in aortic tissue from apoE-/-/LTbR-/- mice. Moreover, bone marrow chimeras demonstrated that LTbR deficiency in hematopoietic cells mediated the atheroprotection. Furthermore, during atheroprogression, apoE-/- mice exhibited increased concentrations of cytokines, for example, Ccl5, whereas apoE-/-/LTbR-/- mice did not. Despite this decreased plaque macrophage content, flow cytometric analysis showed that the numbers of circulating lymphocyte antigen 6C (Ly6C)low monocytes were markedly elevated in apoE-/-/LTbR-/- mice. The influx of these cells into atherosclerotic lesions was significantly reduced, whereas apoptosis and macrophage proliferation in atherosclerotic lesions were unaffected. Gene array analysis pointed to chemokine (C-C motif) receptor 5 as the most regulated pathway in isolated CD115+ cells in apoE-/-/LTbR-/- mice. Furthermore, stimulating monocytes from apoE-/- mice with agonistic anti-LTbR antibody or the natural ligand lymphotoxin-α1β2, increased Ccl5 mRNA expression. Conclusions: These findings suggest that LTbR plays a role in macrophage-driven inflammation in atherosclerotic lesions, probably by augmenting the Ccl5-mediated recruitment of monocytes. © 2015 American Heart Association, Inc.

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