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

Oliver Soehnlein*, Maik Drechsler, Yvonne Doering, Dirk Lievens, Helene Hartwig, Klaus Kemmerich, Almudena Ortega-Gomez, Manuela Mandl, Santosh Vijayan, Delia Projahn, Christoph D. Garlichs, Rory R. Koenen, Mihail Hristov, Esther Lutgens, Alma Zernecke, Christian Weber

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

141 Citations (Web of Science)

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.
Original languageEnglish
Pages (from-to)471-481
JournalEMBO Molecular Medicine
Volume5
Issue number3
DOIs
Publication statusPublished - Mar 2013

Keywords

  • atherosclerosis
  • chemokine
  • mobilization
  • monocyte
  • recruitment

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