CCR6 selectively promotes monocyte mediated inflammation and atherogenesis in mice

Helga D Manthey, Clément Cochain, Stefanie Barnsteiner, Ela Karshovska, Jaroslav Pelisek, Miriam Koch, Sweena M Chaudhari, Martin Busch, Hans-Henning Eckstein, Christian Weber, Rory R Koenen, Alma Zernecke*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1267-77
Number of pages11
JournalThrombosis and Haemostasis
Volume110
Issue number6
DOIs
Publication statusPublished - Dec 2013
Externally publishedYes

Keywords

  • Animals
  • Atherosclerosis/immunology
  • Cell Adhesion/genetics
  • Cell Movement/genetics
  • Cells, Cultured
  • Diet, High-Fat
  • Disease Models, Animal
  • Disease Susceptibility
  • Inflammation/genetics
  • Macrophages/immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes/immunology
  • Receptors, CCR6/genetics
  • Receptors, Cell Surface/metabolism
  • Receptors, LDL/genetics
  • T-Lymphocytes/immunology

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