title: CXCR4 blockade induces atherosclerosis by affecting neutrophil function.
abstract: OBJECTIVE
  The SDF-1α/CXCR4 dyad was previously shown by us and others to be instrumental in intimal hyperplasia as well as early stage atherosclerosis. We here sought to investigate its impact on clinically relevant stages of atherosclerosis in mouse and man.
  
  
  RESULTS
  Immunohistochemical analysis of CXCR4 expression in human atherosclerotic lesions revealed a progressive accumulation of CXCR4(+) cells during plaque progression. To address causal involvement of CXCR4 in advanced stages of atherosclerosis we reconstituted LDLr(-/-) mice with autologous bone marrow infected with lentivirus encoding SDF-1α antagonist or CXCR4 degrakine, which effects proteasomal degradation of CXCR4. Functional CXCR4 blockade led to progressive plaque expansion with disease progression, while also promoting intraplaque haemorrhage. Moreover, CXCR4 knockdown was seen to augment endothelial adhesion of neutrophils. Concordant with this finding, inhibition of CXCR4 function increased adhesive capacity and reduced apoptosis of neutrophils and resulted in hyperactivation of circulating neutrophils. Compatible with a role of the neutrophil CXCR4 in end-stage atherosclerosis, CXCR4 expression by circulating neutrophils was lowered in patients with acute cardiovascular syndromes.
  
  
  CONCLUSIONS
  In conclusion, CXCR4 contributes to later stages of plaque progression by perturbing neutrophil function.
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. Electronic address: i.bot@lacdr.leidenuniv.nl.
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.affiliation: Experimental Vascular Pathology Group, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Isabelle T M N
authors.initials: IT
authors.lastname: Daissormont
authors.affiliation: Rudolf-Virchow-Center/DFG-Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Gijs H M
authors.initials: GH
authors.lastname: van Puijvelde
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Kramp
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.affiliation: Experimental Vascular Pathology Group, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Sluimer
authors.affiliation: Experimental Vascular Pathology Group, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Manca
authors.affiliation: Experimental Vascular Pathology Group, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Veronica
authors.initials: V
authors.lastname: Hérias
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Marijke M
authors.initials: MM
authors.lastname: Westra
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: Bot
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van Santbrink
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.affiliation: Department of Microbiology & Immunology, Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology School of Medicine, The University of North Carolina, Chapel Hill, NC 27599-7295.
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Neurology, Rikshospitalet University Hospital, University of Oslo, Norway.
authors.forename: Mona
authors.initials: M
authors.lastname: Skjelland
authors.affiliation: Department of Cardiology, Rikshospitalet University Hospital, University of Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.affiliation: Department of Internal Medicine, Rikshospitalet University Hospital, University of Oslo, Norway.
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.affiliation: Department of Internal Medicine, Rikshospitalet University Hospital, University of Oslo, Norway.
authors.forename: Paul
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Rory R
authors.initials: RR
authors.lastname: Koenen
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Experimental Vascular Pathology Group, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006470:Hemorrhage / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D011973:Receptors, LDL; D046988:Proteasome Endopeptidase Complex
keywords: CXCR4; SDF-1α; atherosclerosis; neutrophils; senescence