CXCR2- and E-selectin-induced neutrophil arrest during inflammation in vivo.
The signaling events leading to the activation of integrins and firm arrest of rolling neutrophils in inflamed venules have yet to be elucidated. In vitro assays suggest that both E-selectin and chemokines can trigger arrest of rolling neutrophils, but E-selectin(-/-) mice have normal levels of adherent neutrophils in inflamed venules. To test whether chemokine-induced neutrophil arrest in vivo can be unmasked by blocking E-selectin, we investigated neutrophil adhesion in inflamed cremaster muscle venules in tumor necrosis factor (TNF)-alpha-treated CXCR2(-/-) or wild-type (WT) mice injected with E-selectin blocking monoclonal antibody (mAb) 9A9. To block chemokine receptor signaling, we investigated E-selectin(-/-) or WT mice treated with pertussis toxin (PTx) intravenously. Neutrophil adhesion was unchanged in CXCR2(-/-), E-selectin(-/-), PTx-treated WT, or mAb 9A9-treated WT mice. However, TNF-alpha-induced neutrophil adhesion was almost completely abrogated in E-selectin(-/-) mice treated with PTx and significantly reduced in CXCR2(-/-) mice treated with the E-selectin blocking mAb. In thioglycollate-induced peritonitis, PTx treatment blocked neutrophil recruitment into the peritoneum of E-selectin(-/-) mice, but had only a partial effect in WT animals. These data show that E-selectin- and chemokine-mediated arrest mechanisms are overlapping in this model and identify CXCR2 as an important neutrophil arrest chemokine in vivo.
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
Michael L
ML
Smith
Timothy S
TS
Olson
Klaus
K
Ley
D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D019040:E-Selectin / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009132:Muscles / Q000098:blood supply* / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology*; D037342:Pertussis Toxin; D023063:Receptors, Interleukin-8B / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha; D014699:Venules / Q000276:immunology
D019040:E-Selectin; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha; D037342:Pertussis Toxin