title: Genetic deletion of chemokine receptor Ccr7 exacerbates atherogenesis in ApoE-deficient mice.
abstract: OBJECTIVE
  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.
  
  
  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-β) was significantly decreased, suggesting an imbalance of T cell responses in these mice.
  
  
  CONCLUSIONS
  Our data suggest that genetic deletion of Ccr7 exacerbates atherosclerosis by increasing T cell accumulation in atherosclerotic lesions.
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases,  National Institutes of Health, 9000 Rockville Pike, Bldg 10, Rm11N113, Bethesda, MD 20892,  USA.
authors.forename: Wuzhou
authors.initials: W
authors.lastname: Wan
authors.forename: Michail S
authors.initials: MS
authors.lastname: Lionakis
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Ester
authors.initials: E
authors.lastname: Roffê
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016026:Bone Marrow Transplantation / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D018664:Interleukin-12 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054400:Receptors, CCR7 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013601:T-Lymphocytes / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000097:blood
chemical_list: D001057:Apolipoproteins E; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D016212:Transforming Growth Factor beta; D018664:Interleukin-12