The chemokine receptors CXCR1/CXCR2 modulate antigen‐induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature

• DOI: 10.1002/art.23622
• Publication Date: 2008-08-02T05:17:08Z
• Authors: Fernanda M. Coelho; Vanessa Pinho; Flávio A. Amaral; Daniela Sachs; Vívian V. Costa; David H. Rodrigues; Angélica T. Vieira; Tarcília A. Silva; Daniele G. Souza; Riccardo Bertini; Antônio L. Teixeira; Mauro M. Teixeira
• Keywords: Male; Mesylates; Sulfonamides; 0303 health sciences; Neutrophils; Tumor Necrosis Factor-alpha; Synovial Membrane; Benzeneacetamides; Arthritis, Experimental; Receptors, Interleukin-8B; Receptors, Interleukin-8A; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Adjuvants, Immunologic; Cell Movement; Cell Adhesion; Animals; Endothelium, Vascular; Peroxidase

AbstractObjectiveThe 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).MethodsAIA 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 α (TNFα) 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.ResultsAntigen challenge in immunized mice induced production of TNFα, 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 TNFα production, hypernociception, and the overall severity of the disease in the tissue.ConclusionBlockade 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.