title: Mast cells mediate neutrophil recruitment during atherosclerotic plaque progression.
abstract: OBJECTIVE
  Activated mast cells have been identified in the intima and perivascular tissue of human atherosclerotic plaques. As mast cells have been described to release a number of chemokines that mediate leukocyte fluxes, we propose that activated mast cells may play a pivotal role in leukocyte recruitment during atherosclerotic plaque progression.
  
  
  RESULTS
  Systemic IgE-mediated mast cell activation in apoE(-/-)μMT mice resulted in an increase in atherosclerotic lesion size as compared to control mice, and interestingly, the number of neutrophils was highly increased in these lesions. In addition, peritoneal mast cell activation led to a massive neutrophil influx into the peritoneal cavity in C57Bl6 mice, whereas neutrophil numbers in mast cell deficient Kit(W(-sh)/W(-sh)) mice were not affected. Within the newly recruited neutrophil population, increased levels of CXCR2(+) and CXCR4(+) neutrophils were observed after mast cell activation. Indeed, mast cells were seen to contain and release CXCL1 and CXCL12, the ligands for CXCR2 and CXCR4. Intriguingly, peritoneal mast cell activation in combination with anti-CXCR2 receptor antagonist resulted in decreased neutrophil recruitment, thus establishing a prominent role for the CXCL1/CXCR2 axis in mast cell-mediated neutrophil recruitment.
  
  
  CONCLUSIONS
  Our data suggest that chemokines, and in particular CXCL1, released from activated mast cells induce neutrophil recruitment to the site of inflammation, thereby aggravating the ongoing inflammatory response and thus affecting plaque progression and destabilization.
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: Wezel
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: H Maxime
authors.initials: HM
authors.lastname: Lagraauw
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Daniël
authors.initials: D
authors.lastname: van der Velden
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
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: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: i.bot@lacdr.leidenuniv.nl.
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
mesh_terms: D000818:Animals; D001011:Aorta / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D007073:Immunoglobulin E / Q000008:administration & dosage / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D019899:Paracrine Communication; D058226:Plaque, Atherosclerotic; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; C514936:CXCR4 protein, mouse; D054360:Chemokine CXCL1; D054377:Chemokine CXCL12; C475895:Cxcl1 protein, mouse; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; D007073:Immunoglobulin E
keywords: Atherosclerotic plaque development and progression; Chemokines; Influx; Mast cells; Neutrophils; Recruitment