Maria Grandoch1, Kathrin Feldmann2, Joachim R Göthert2, Lena S Dick2, Susanne Homann2, Christina Klatt2, Julia K Bayer2, Jan N Waldheim2, Berit Rabausch2, Nadine Nagy2, Alexander Oberhuber2, René Deenen2, Karl Köhrer2, Stefan Lehr2, Bernhard Homey2, Klaus Pfeffer2, Jens W Fischer2. 1. From the Institut für Pharmakologie und Klinische Pharmakologie (M.G., K.F., L.S.D., S.H., C.K., J.K.B., J.N.W., B.R., N.N., J.W.F.), Cardiovascular Research Institute Düsseldorf (CARID) (M.G., K.F., L.S.D., S.H., C.K., J.K.B., J.N.W., B.R., N.N., J.W.F.), Klinik für Gefäß- und Endovaskularchirurgie (A.O.), Biologisch-Medizinisches Forschungszentrum (BMFZ) (R.D., K.K.), Hautklinik (B.H.), and Institut für Medizinische Mikrobiologie und Krankenhaushygiene (K.P.), Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; Klinik für Hämatologie, Universitätsklinikum Essen, Westdeutsches Tumorzentrum (WTZ), Essen, Germany (J.R.G.); and Institut für Klinische Biochemie und Pathobiochemie, Deutsches Diabetes Zentrum, Düsseldorf, Germany (S.L.). Maria.Grandoch@uni-duesseldorf.de. 2. From the Institut für Pharmakologie und Klinische Pharmakologie (M.G., K.F., L.S.D., S.H., C.K., J.K.B., J.N.W., B.R., N.N., J.W.F.), Cardiovascular Research Institute Düsseldorf (CARID) (M.G., K.F., L.S.D., S.H., C.K., J.K.B., J.N.W., B.R., N.N., J.W.F.), Klinik für Gefäß- und Endovaskularchirurgie (A.O.), Biologisch-Medizinisches Forschungszentrum (BMFZ) (R.D., K.K.), Hautklinik (B.H.), and Institut für Medizinische Mikrobiologie und Krankenhaushygiene (K.P.), Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; Klinik für Hämatologie, Universitätsklinikum Essen, Westdeutsches Tumorzentrum (WTZ), Essen, Germany (J.R.G.); and Institut für Klinische Biochemie und Pathobiochemie, Deutsches Diabetes Zentrum, Düsseldorf, Germany (S.L.).
Abstract
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.
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 LTbRdeficiency 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.
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