Deficiency in Lymphotoxin β Receptor Protects From Atherosclerosis in apoE-Deficient Mice
| Autor: | Kathrin Feldmann, Bernhard Homey, Lena S. Dick, René Deenen, Joachim R. Göthert, Jens W. Fischer, Nadine Nagy, Jan N. Waldheim, Susanne Homann, Alexander Oberhuber, Maria Grandoch, Klaus Pfeffer, Berit Rabausch, Christina Klatt, Stefan Lehr, Karl Köhrer, Julia K. Bayer |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Apolipoprotein E
Chemokine Time Factors Transcription Genetic Neutrophils Physiology Aortic Diseases Medizin Inflammation Monocytes CCL5 Apolipoproteins E Lymphotoxin beta Receptor medicine Animals Antigens Ly Chemokine CCL5 Aorta Cells Cultured Bone Marrow Transplantation Mice Knockout B-Lymphocytes Transplantation Chimera biology Chemotaxis Macrophages Monocyte Lymphotoxin alpha1 beta2 Heterotrimer Atherosclerosis Molecular biology Plaque Atherosclerotic Mice Inbred C57BL Disease Models Animal Lymphotoxin medicine.anatomical_structure Gene Expression Regulation Immunology biology.protein medicine.symptom Cardiology and Cardiovascular Medicine Lymphotoxin beta receptor Macrophage proliferation |
| Zdroj: | Circulation Research. 116 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.116.305723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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