• Open Access

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

Authors

  • Oliver Soehnlein,

    Corresponding author
    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
    2. Department of Pathology, Academic Medical Center Amsterdam, University of Amsterdam, the Netherlands
    3. Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Germany
    • Tel: +49 89 5160 4673; Fax: +49 89 5160 4352
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    • These authors contributed equally to this work.

  • Maik Drechsler,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
    2. Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Germany
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    • These authors contributed equally to this work.

  • Yvonne Döring,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
    2. Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Germany
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  • Dirk Lievens,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
    2. Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Germany
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  • Helene Hartwig,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
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  • Klaus Kemmerich,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
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  • Almudena Ortega-Gómez,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
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  • Manuela Mandl,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
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  • Santosh Vijayan,

    1. Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Germany
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  • Delia Projahn,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
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  • Christoph D. Garlichs,

    1. Department of Cardiology, Friedrich-Alexander University Erlangen, Germany
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  • Rory R. Koenen,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
    2. Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
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  • Mihail Hristov,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
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  • Esther Lutgens,

    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
    2. Department of Medical Biochemistry, Academic Medical Center Amsterdam, University of Amsterdam, the Netherlands
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  • Alma Zernecke,

    1. Rudolf-Virchow-Center/DFG Research Center for Experimental Biomedicine, University of Würzburg, Germany
    2. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
    3. Present address: Department of Vascular Surgery, Technical University Munich, Germany
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    • These authors contributed equally to this work.

  • Christian Weber

    Corresponding author
    1. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany
    2. Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Germany
    3. Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
    4. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
    • Tel: +49 89 5160 4350; Fax: +49 89 5160 4352
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    • These authors contributed equally to this work.


Abstract

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.

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