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Genetic deletion of chemokine receptor Ccr7 exacerbates atherogenesis in ApoE-deficient mice.

Cardiovascular research (2012-11-28)
Wuzhou Wan, Michail S Lionakis, Qian Liu, Ester Roffê, Philip M Murphy
RESUMEN

Recent evidence suggests that both Ccr7 and its ligands, Ccl19 and Ccl21, are present in mouse and human atherosclerotic plaques; however, the role of Ccr7 in atherogenesis is still controversial. Here, we addressed this question by using the classic apolipoprotein E-deficient (ApoE(-/-)) mouse model of atherosclerosis. Ccr7(-/-)ApoE(-/-) double knockout mice and Ccr7(+/+)ApoE(-/-) littermates were generated and maintained on a high-fat Western diet for 8 weeks to induce atherosclerosis. Ccr7(-/-)ApoE(-/-) mice showed an ~80% increase in atherosclerotic lesion size in the whole aorta and a two-fold increase in the aortic root compared with Ccr7(+/+)ApoE(-/-) mice. Ccr7(-/-)ApoE(-/-) mice had increased T cells in the blood, bone marrow, and spleen, as well as in atherosclerotic lesions. Competitive repopulation experiments revealed that T cells from Ccr7(-/-)ApoE(-/-) mice migrated poorly into lymph nodes but better into mouse aortas compared with T cells from Ccr7(+/+)ApoE(-/-) mice. Transplantation of the bone marrow from Ccr7(-/-)ApoE(-/-) mice into lethally irradiated Ccr7(+/+)ApoE(-/-) mice resulted in ~60% more atherosclerotic lesions compared with Ccr7(+/+)ApoE(-/-) donor bone marrow, suggesting that exacerbation was mediated by a Ccr7(+) bone marrow-derived cell(s). Furthermore, in Ccr7(-/-)ApoE(-/-) mice the serum level of IL-12 was markedly increased, whereas the level of transforming growth factor beta (TGF-β) was significantly decreased, suggesting an imbalance of T cell responses in these mice. Our data suggest that genetic deletion of Ccr7 exacerbates atherosclerosis by increasing T cell accumulation in atherosclerotic lesions.

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Roche
Colagenasa B, from Clostridium histolyticum
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