These authors contributed equally to this work.
Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes
Version of Record online: 18 FEB 2013
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.
EMBO Molecular Medicine
Volume 5, Issue 3, pages 471–481, March 2013
How to Cite
Soehnlein, O., Drechsler, M., Döring, Y., Lievens, D., Hartwig, H., Kemmerich, K., Ortega-Gómez, A., Mandl, M., Vijayan, S., Projahn, D., Garlichs, C. D., Koenen, R. R., Hristov, M., Lutgens, E., Zernecke, A. and Weber, C. (2013), Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes. EMBO Mol Med, 5: 471–481. doi: 10.1002/emmm.201201717
- Issue online: 5 MAR 2013
- Version of Record online: 18 FEB 2013
- Manuscript Accepted: 20 DEC 2012
- Manuscript Revised: 19 DEC 2012
- Manuscript Received: 9 JUL 2012
- Funded Access
We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical (inflammatory/Gr1hi) or non-classical (resident/Gr1lo) 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.