title: Activated platelets promote increased monocyte expression of CXCR5 through prostaglandin E2-related mechanisms and enhance the anti-inflammatory effects of CXCL13.
abstract: BACKGROUND
  We have previously shown that the homeostatic chemokine CXCL13 is up-regulated in monocytes in atherosclerosis, mediating anti-apoptotic and anti-inflammatory effects.
  
  
  OBJECTIVE
  To investigate the regulation of CXCL13s receptor, CXCR5.
  
  
  METHODS
  In vitro studies in THP-1 and primary monocytes and studies of CXCR5 expression in thrombus material obtained at the site of plaque rupture during myocardial infarction (MI).
  
  
  RESULTS
  Our major findings were: (i) toll-like receptor agonists and particularly β-adrenergic receptor activation and releasate from thrombin-activated platelets increased CXCR5 mRNA levels in monocytes. (ii) The platelet-mediated induction of CXCR5 involved prostaglandin E2/cAMP/protein kinase A-dependent as well as RANTES-dependent pathways with NFκB activation as a potential common down-stream mediator. (iii) Releasate from thrombin-activated platelets augmented the anti-inflammatory effects of CXCL13 in monocytes at least partly by enhancing the effects of CXCL13 on CXCR5 expression. (iv) We found strong immunostaining of CXCR5 in thrombus material obtained at the site of plaque rupture in patients with ST elevation MI (STEMI) and in unstable carotid lesions, co-localized with platelets.
  
  
  CONCLUSIONS
  Our findings suggest that platelet-mediated signaling through CXCR5 may be active in vivo during plaque destabilization, potentially representing a counteracting mechanism to inflammation.
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: Bente.Halvorsen@rr-research.no.
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Smedbakken
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Annika E
authors.initials: AE
authors.lastname: Michelsen
authors.affiliation: Department of Neurology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Mona
authors.initials: M
authors.lastname: Skjelland
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Vigdis
authors.initials: V
authors.lastname: Bjerkeli
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ellen Lund
authors.initials: EL
authors.lastname: Sagen
authors.affiliation: Department of Infectious Diseases, Oslo University Hospital Ullevål, Oslo, Norway; Centre for Molecular Medicine Norway, Nordic EMBL Partnership and Biotechnology Centre, Oslo University Hospital and University of Oslo, Oslo, Norway; Biotechnology Centre, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
authors.affiliation: Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Bendz
authors.affiliation: Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Sverre
authors.initials: S
authors.lastname: Holm
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, Netherlands.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
mesh_terms: D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058226:Plaque, Atherosclerotic; D015539:Platelet Activation; D054380:Receptors, CXCR5 / Q000235:genetics / Q000378:metabolism*; D012422:Rupture, Spontaneous; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism
chemical_list: C483024:CCL5 protein, human; C110663:CXCL13 protein, human; C095085:CXCR5 protein, human; D018946:Chemokine CCL5; D054382:Chemokine CXCL13; D054380:Receptors, CXCR5; D013917:Thrombin; D015232:Dinoprostone
keywords: Atherothrombosis; Chemokines; Inflammation; Monocytes; Platelets