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

Abstract

AimsRecent 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 resultsCcr7-/-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.ConclusionOur data suggest that genetic deletion of Ccr7 exacerbates atherosclerosis by increasing T cell accumulation in atherosclerotic lesions. © 2012 The Author.