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


ABSTRACT:

Aims

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.

Methods and results

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-?) was significantly decreased, suggesting an imbalance of T cell responses in these mice.

Conclusion

Our data suggest that genetic deletion of Ccr7 exacerbates atherosclerosis by increasing T cell accumulation in atherosclerotic lesions.

SUBMITTER: Wan W 

PROVIDER: S-EPMC3567784 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Wan Wuzhou W   Lionakis Michail S MS   Liu Qian Q   Roffê Ester E   Murphy Philip M PM  

Cardiovascular research 20121124 3


<h4>Aims</h4>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.<h4>Methods and results</h4>Ccr7(-/-)ApoE(-/-) double knockout mice and Ccr7(+/+)ApoE(-/-) littermates were generated and maintained on a high-fat Western diet for 8  ...[more]

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