Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes.

Abstract

We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical (inflammatory/Gr1(hi) ) or non-classical (resident/Gr1(lo) ) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient (Apoe(-/-) ) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient Apoe(-/-) mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or CX3 CR1 in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment.

• Authors: Oliver Soehnlein, Maik Drechsler, Yvonne Döring, Dirk Lievens, Helene Hartwig, Klaus Kemmerich, Almudena Ortega-Gómez, Manuela Mandl, Santosh Vijayan, Delia Projahn, Christoph D Garlichs, Rory R Koenen, Mihail Hristov, Esther Lutgens, Alma Zernecke, Christian Weber
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 5 Issue 3 Pg. 471-81 (Mar 2013) ISSN: 1757-4684 [Electronic] England
• PMID: 23417922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Chemical References

• Apolipoproteins E
• Ccr1 protein, mouse
• Chemokine CXCL1
• Cxcl1 protein, mouse
• Receptors, CCR1
• Receptors, CCR5
• Receptors, Chemokine
• Receptors, Interleukin-8B

Topics

• Adoptive Transfer
• Animals
• Aorta (immunology, metabolism, pathology)
• Aortic Diseases (etiology, genetics, immunology, metabolism, pathology)
• Apolipoproteins E (deficiency, genetics)
• Apoptosis
• Atherosclerosis (etiology, genetics, immunology, metabolism, pathology)
• Carotid Arteries (immunology, metabolism, pathology)
• Carotid Artery Diseases (etiology, genetics, immunology, metabolism, pathology)
• Chemokine CXCL1 (metabolism)
• Chemotaxis, Leukocyte
• Diet, High-Fat
• Disease Models, Animal
• Disease Progression
• Leukocyte Count
• Leukocyte Reduction Procedures
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (classification, immunology, transplantation)
• Receptors, CCR1 (metabolism)
• Receptors, CCR5 (metabolism)
• Receptors, Chemokine (deficiency, genetics, metabolism)
• Receptors, Interleukin-8B (metabolism)
• Signal Transduction
• Time Factors