Deficiency in lymphotoxin β receptor protects from atherosclerosis in apoE-deficient mice.

Lymphotoxin β receptor (LTbR) regulates immune cell trafficking and communication in inflammatory diseases. However, the role of LTbR in atherosclerosis is still unclear. The aim of this study was to elucidate the role of LTbR in atherosclerosis. 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. These findings suggest that LTbR plays a role in macrophage-driven inflammation in atherosclerotic lesions, probably by augmenting the Ccl5-mediated recruitment of monocytes.

Grandoch M ，Feldmann K ，Göthert JR ，Dick LS ，Homann S ，Klatt C ，Bayer JK ，Waldheim JN ，Rabausch B ，Nagy N ，Oberhuber A ，Deenen R ，Köhrer K ，Lehr S ，Homey B ，Pfeffer K ，Fischer JW ... -  《-》

Pharmacological inhibition of the chemokine receptor, CX3CR1, reduces atherosclerosis in mice.

Poupel L ，Boissonnas A ，Hermand P ，Dorgham K ，Guyon E ，Auvynet C ，Charles FS ，Lesnik P ，Deterre P ，Combadiere C ... -  《-》

Endothelin-1 overexpression exacerbates atherosclerosis and induces aortic aneurysms in apolipoprotein E knockout mice.

Li MW ，Mian MO ，Barhoumi T ，Rehman A ，Mann K ，Paradis P ，Schiffrin EL ... -  《-》

The anti-inflammatory vasostatin-2 attenuates atherosclerosis in ApoE(-/-) mice and inhibits monocyte/macrophage recruitment.

Xiong W ，Wang X ，Dai D ，Zhang B ，Lu L ，Tao R ... -  《-》

Map3k8 Modulates Monocyte State and Atherogenesis in ApoE-/- Mice.

Map3k8 (Cot/Tpl2) activates the MKK1/2-ERK1/2, MAPK pathway downstream from interleukin-1R, tumor necrosis factor-αR, NOD-2R (nucleotide-binding oligomerization domain-like 2R), adiponectinR, and Toll-like receptors. Map3k8 plays a key role in innate and adaptive immunity and influences inflammatory processes by modulating the functions of different cell types. However, its role in atherogenesis remains unknown. In this study, we analyzed the role of this kinase in this pathology. We show here that Map3k8 deficiency results in smaller numbers of Ly6ChighCD11clow and Ly6ClowCD11chigh monocytes in ApoE-/- mice fed a high-fat diet (HFD). Map3k8-/-ApoE-/- monocytes displayed high rates of apoptosis and reduced amounts of Nr4a1, a transcription factor known to modulate apoptosis in Ly6ClowCD11chigh monocytes. Map3k8-/-ApoE-/- splenocytes and macrophages showed irregular patterns of cytokine and chemokine expression. Map3k8 deficiency altered cell adhesion and migration in vivo and decreased CCR2 expression, a determinant chemokine receptor for monocyte mobilization, on circulating Ly6ChighCD11clow monocytes. Map3k8-/-ApoE-/- mice fed an HFD showed decreased cellular infiltration in the atherosclerotic plaque, with low lipid content. Lesions had similar size after Map3k8+/+ApoE-/- bone marrow transplant into Map3k8-/-ApoE-/- and Map3k8+/+ApoE-/- mice fed an HFD, whereas smaller plaques were observed after the transplantation of bone marrow lacking both ApoE and Map3k8. Map3k8 decreases apoptosis of monocytes and enhances CCR2 expression on Ly6ChighCD11clow monocytes of ApoE-/- mice fed an HFD. These findings explain the smaller aortic lesions in ApoE-/- mice with Map3k8-/-ApoE-/- bone marrow cells fed an HFD, supporting further studies of Map3k8 as an antiatherosclerotic target.

Sanz-Garcia C ，Sánchez Á ，Contreras-Jurado C ，Cales C ，Barranquero C ，Muñoz M ，Merino R ，Escudero P ，Sanz MJ ，Osada J ，Aranda A ，Alemany S ... -  《-》