Deficiency in Lymphotoxin β Receptor Protects From Atherosclerosis in apoE-Deficient Mice. Issue 8 (10th April 2015)

• Record Type: Journal Article
• Authors: Grandoch, Maria; Feldmann, Kathrin; Göthert, Joachim R.; Dick, Lena S.; Homann, Susanne; Klatt, Christina; Bayer, Julia K.; Waldheim, Jan N.; Rabausch, Berit; Nagy, Nadine; Oberhuber, Alexander; Deenen, René; Köhrer, Karl; Lehr, Stefan; Homey, Bernhard; Pfeffer, Klaus; Fischer, Jens W.
• Is Part Of: Circulation research. Volume 116:Issue 8(2015)
• Publication Date: 2015-04-10
• Subjects: Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.116.305723
• Languages: English
• ISSNs: 0009-7330

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title> <underline>Rationale:</underline> </title> <p>Lymphotoxin β receptor (LTbR) regulates immune cell trafficking and communication in inflammatory diseases. However, the role of LTbR in atherosclerosis is still unclear.</p> </sec> <sec> <title> <underline>Objective:</underline> </title> <p>The aim of this study was to elucidate the role of LTbR in atherosclerosis.</p> </sec> <sec> <title> <underline>Methods and Results:</underline> </title> <p>After 15 weeks of feeding a Western-type diet, mice double-deficient in apolipoprotein E and LTbR (apoE<sup>−/−</sup>/LTbR<sup>−/−</sup>) exhibited lower aortic plaque burden than did apoE<sup>−/−</sup> 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 (<italic>Ccl5</italic>) and other chemokines were transcriptionally downregulated in aortic tissue from apoE<sup>−/−</sup>/LTbR<sup>−/−</sup> mice. Moreover, bone marrow chimeras demonstrated that LTbR deficiency in hematopoietic cells mediated the atheroprotection. Furthermore, during atheroprogression, apoE<sup>−/−</sup> mice exhibited increased concentrations of cytokines, for example, Ccl5, whereas apoE<sup>−/−</sup>/LTbR<sup>−/−</sup> mice did not. Despite this decreased plaque macrophage content, flow cytometric analysis showed that the numbers of circulating lymphocyte antigen 6C (Ly6C)<sup>low</sup> monocytes were markedly elevated in apoE<sup>−/−</sup>/LTbR<sup>−/−</sup> 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<sup>+</sup> cells in apoE<sup>−/−</sup>/LTbR<sup>−/−</sup> mice. Furthermore, stimulating monocytes from apoE<sup>−/−</sup> mice with agonistic anti-LTbR antibody or the natural ligand lymphotoxin-α1β2, increased <italic>Ccl5</italic> mRNA expression.</p> </sec> <sec> <title> <underline>Conclusions:</underline> </title> <p>These findings suggest that LTbR plays a role in macrophage-driven inflammation in atherosclerotic lesions, probably by augmenting the Ccl5-mediated recruitment of monocytes.</p> </sec> </abstract>