title: Endothelial cell-borne platelet bridges selectively recruit monocytes in human and mouse models of vascular inflammation.
abstract: OBJECTIVE
  Cells of the monocyte lineage are the most abundant inflammatory cells found in atherosclerotic lesions. Dominance of the inflammatory infiltrate by monocytes indicates that there is a disease-driven mechanism supporting their selective recruitment. Previous studies have demonstrated that interactions between endothelial cells (ECs) and platelets may promote monocyte recruitment. In this study, we sought to expand on this knowledge using a complex coculture model of the diseased vessel wall.
  
  
  RESULTS
  Using primary human cells in an in vitro flow-based adhesion assay, we found that secretory arterial smooth muscle cells (SMCs), cocultured with ECs, promote preferential recruitment of monocytes from blood in a TGF-β1-dependent manner. Approximately 85% of leucocytes recruited to the endothelium were CD14(+). Formation of adhesive platelet bridges on ECs was essential for monocyte recruitment as platelet removal or inhibition of adhesion to the ECs abolished monocyte recruitment. Monocytes were recruited from flow by platelet P-selectin and activated by EC-derived CC chemokine ligand 2 (CCL2), although the presentation of CCL2 to adherent monocytes was dependent upon platelet activation and release of CXC chemokine ligand 4 (CXCL4). In an intravital model of TGF-β1-driven vascular inflammation in mice, platelets were also necessary for efficient leucocyte recruitment to vessels of the microcirculation in the cremaster muscle.
  
  
  CONCLUSIONS
  In this study, we have demonstrated that stromal cells found within the diseased artery wall may promote the preferential recruitment of monocytes and this is achieved by establishing a cascade of interactions between SMCs, ECs, platelets, and monocytes.
authors.affiliation: Centre for Cardiovascular Sciences, Institute for Biomedical Research, The Medical School, The University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kuckleburg
authors.forename: Clara M
authors.initials: CM
authors.lastname: Yates
authors.forename: Neena
authors.initials: N
authors.lastname: Kalia
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Nash
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.forename: George Ed
authors.initials: GE
authors.lastname: Rainger
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000276:immunology* / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation; D010973:Platelet Adhesiveness; D010978:Platelet Factor 4 / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; C546937:SELP protein, human; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D010978:Platelet Factor 4