CCR6 selectively promotes monocyte mediated inflammation and atherogenesis in mice

Summary

The chemokine receptor CCR6 is expressed by various cell subsets implicated in atherogenesis, such as monocytes, Th17 and regulatory T cells. In order to further define the role of CCR6 in atherosclerosis, CCR6-deficient (Ccr6 ^-/-) mice were crossed with low-density lipoprotein receptor-deficient (Ldlr ^-/-) mice to generate atherosclerosis-prone mice deficient in CCR6. Compared to Ldlr ^-/- controls, atherosclerotic burden in the aortic sinus and aorta were reduced in Ccr6 ^-/- Ldlr ^-/- mice fed a high fat diet, associated with a profound depression in lesional macrophage accumulation. Local and systemic distributions of T cells, including frequencies of Th1, Th17 and regulatory T cells were unaltered. In contrast, circulating counts of both Gr-1^high and Gr1^low monocytes were reduced in Ccr6 ^-/- Ldlr ^-/- mice. Moreover, CCR6 was revealed to promote monocyte adhesion to inflamed endothelium in vitro and leukocyte adhesion to carotid arteries in vivo. Finally, CCR6 selectively recruited monocytes but not T cells in an acute inflammatory air pouch model. We here show that CCR6 functions on multiple levels and regulates the mobilisation, adhesion and recruitment of monocytes/macrophages to the inflamed vessel, thereby promoting atherosclerosis, but is dispensable for hypercholesterolaemia-associated adaptive immune priming. Targeting CCR6 or its ligand CCL20 may therefore be a promising therapeutic strategy to alleviate atherosclerosis.

Note: The review process for this manuscript was fully handled by G. Y. H. Lip, Editor in Chief.

Keywords

Atherosclerosis - chemokines - CCR6 - monocyte - recruitment

^* Equal contribution by these authors.

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