title: Adhesive Mechanisms of Histone-Induced Neutrophil-Endothelium Interactions in the Muscle Microcirculation.
abstract: BACKGROUND
  Extracellular histones released during cell damage have the capacity to cause tissue injury associated with increased leukocyte accumulation. However, the molecular mechanisms regulating histone-induced leukocyte recruitment remain elusive. The objective of this study was to examine the role of adhesion molecules in histone-dependent leukocyte accumulation by use of intravital microscopy of the mouse cremaster microcirculation.
  
  
  METHODS
  Histone 3 and TNF-α were intrascrotally administered, and anti-P-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1) antibody and neutrophil depletion antibody were injected intravenously or intraperitoneally.
  
  
  RESULTS
  Intrascrotal injection of histone 3 dose-dependently increased leukocyte recruitment. Neutrophil depletion abolished intravascular and extravascular leukocytes after histone 3 challenge, suggesting that neutrophils were the dominating leukocyte subtype responding to histone stimulation. Pretreatment with an anti-P-selectin and an anti-PSGL-1 antibody abolished histone-stimulated neutrophil rolling, adhesion and emigration. When the anti-P-selectin or the anti-PSGL-1 antibody was administrated after histone 3 stimulation, neutrophil rolling was reduced, whereas the number of firmly adherent and emigrated neutrophils were unchanged, suggesting that the inhibitory effect of blocking P-selectin and PSGL-1 on neutrophil adhesion and recruitment was due to the reduction in neutrophil rolling. Moreover, pretreatment with antibodies against Mac-1 and LFA-1 had no effect of neutrophil rolling but abolished adhesion and emigration evoked by histone 3. Thus, our data demonstrate that P-selectin and PSGL-1 play an important role in histone-induced inflammatory cell recruitment by mediating neutrophil rolling as a precondition for histone-provoked firm adhesion and emigration in vivo. Moreover, we conclude that both Mac-1 and LFA-1 are critical in supporting histone-provoked firm adhesion of neutrophils to endothelial cells.
  
  
  CONCLUSIONS
  These novel findings define specific selectins and integrins as potential targets for pharmacological intervention in histone-dependent inflammatory diseases.
authors.affiliation: Section of Surgery, Department of Clinical Sciences, Malmx00F6;, Lund University, Malmx00F6;, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Puegge
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Wang
authors.forename: Jonas
authors.initials: J
authors.lastname: Roller
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.forename: Lingtao
authors.initials: L
authors.lastname: Luo
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology*; D006657:Histones / Q000494:pharmacology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D016177:Macrophage-1 Antigen / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D018482:Muscle, Skeletal / Q000098:blood supply*; D009504:Neutrophils / Q000502:physiology*; D019007:P-Selectin / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D006657:Histones; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D019007:P-Selectin; D014409:Tumor Necrosis Factor-alpha