title: The chemokine receptors CXCR1/CXCR2 modulate antigen-induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature.
abstract: OBJECTIVE
  The chemokine receptors CXCR1 and CXCR2 play a role in mediating neutrophil recruitment and neutrophil-dependent injury in several models of inflammation. We undertook this study to investigate the role of these receptors in mediating neutrophil adhesion, subsequent migration, and neutrophil-dependent hypernociception in a murine model of monarticular antigen-induced arthritis (AIA).
  
  
  METHODS
  AIA was induced by administration of antigen into the knee joint of previously immunized mice. Intravital microscopy studies were performed to assess leukocyte rolling and adhesion. Mechanical hypernociception was investigated using an electronic pressure meter. Neutrophil accumulation in the tissue was measured by counting neutrophils in the synovial cavity and assaying myeloperoxidase activity. Levels of tumor necrosis factor alpha (TNFalpha) and the chemokines CXCL1 and CXCL2 were quantified by enzyme-linked immunosorbent assay. Histologic analysis was performed to evaluate the severity of arthritis and leukocyte infiltration.
  
  
  RESULTS
  Antigen challenge in immunized mice induced production of TNFalpha, CXCL1, and CXCL2 and also resulted in neutrophil recruitment, leukocyte rolling and adhesion, and hypernociception. Treatment with reparixin or DF2162 (allosteric inhibitors of CXCR1/CXCR2) decreased neutrophil recruitment, an effect that was associated with marked inhibition of neutrophil adhesion. Drug treatment also inhibited TNFalpha production, hypernociception, and the overall severity of the disease in the tissue.
  
  
  CONCLUSIONS
  Blockade of CXCR1/CXCR2 receptors inhibits neutrophil recruitment by inhibiting the adhesion of neutrophils to synovial microvessels. As a consequence, there is decreased local cytokine production and reduced hypernociception, as well as ameloriation of overall disease in the tissue. These studies suggest a potential therapeutic role for the modulation of CXCR1/CXCR2 receptor signaling in the treatment of arthritis.
authors.affiliation: Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Fernanda M
authors.initials: FM
authors.lastname: Coelho
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pinho
authors.forename: Flávio A
authors.initials: FA
authors.lastname: Amaral
authors.forename: Daniela
authors.initials: D
authors.lastname: Sachs
authors.forename: Vívian V
authors.initials: VV
authors.lastname: Costa
authors.forename: David H
authors.initials: DH
authors.lastname: Rodrigues
authors.forename: Angélica T
authors.initials: AT
authors.lastname: Vieira
authors.forename: Tarcília A
authors.initials: TA
authors.lastname: Silva
authors.forename: Daniele G
authors.initials: DG
authors.lastname: Souza
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bertini
authors.forename: Antônio L
authors.initials: AL
authors.lastname: Teixeira
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D044482:Benzeneacetamides / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology*; D008297:Male; D008698:Mesylates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000473:pathology*; D009195:Peroxidase / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000502:physiology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C528719:4-(2-amino-1-methyl-2-oxoethyl)phenyl trifluoromethanesulfonate; D000276:Adjuvants, Immunologic; D044482:Benzeneacetamides; D008698:Mesylates; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; C490707:reparixin