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

EMBO Molecular Medicine

Oliver Soehnlein⁴  Maik Drechsler²  Yvonne Döring²  Dirk Lievens²  Helene Hartwig²  Klaus Kemmerich²  Almudena Ortega-Gómez²  Manuela Mandl²  Santosh Vijayan³  Delia Projahn²  Christoph D. Garlichs¹  Rory R. Koenen²  Mihail Hristov²  Esther Lutgens²  Alma Zernecke⁵ 

[1] Department of Cardiology, Friedrich-Alexander University Erlangen, Germany;Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany;Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Germany;E-mail address: 关键词: atherosclerosis;    chemokine;    mobilization;    monocyte;    recruitment;   

DOI  :  10.1002/emmm.201201717

来源: Wiley

【 摘 要 】

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 CX₃CR1 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.

【 授权许可】

Unknown   
Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.