Deficiency in Lymphotoxin Beta Receptor Protects from Atherosclerosis in apoE-Deficient Mice
Rationale: Lymphotoxin beta receptor (LTbR) regulates immune cell trafficking and communication in inflammatory diseases. However, the role of LTbR in atherosclerosis is still unclear.
Objective: Aim of the present 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 down-regulated in aortic tissue from apoE-/-/LTbR-/- mice. Moreover, bone marrow chimeras demonstrated that LTbR deficiency in hematopoietic cells mediated the atheroprotection. Furthermore, whereas during atheroprogression apoE-/- mice exhibited increased concentrations of cytokines, e.g. Ccl5, 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 Ccr5 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 LT-alpha1beta2, 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.
- Received November 25, 2014.
- Revision received March 3, 2015.
- Accepted March 4, 2015.