E/P-selectin-deficient mice: an optimal mutation for abrogating antigen but not tumor necrosis factor-alpha-induced immune responses.
Leukocyte recruitment in cremaster microcirculation was visualized by intravital microscopy, either in ovalbumin sensitized and challenged animals, or in response to TNF-alpha. In antigen-challenged mice a significant increase in leukocyte rolling (approximately 50 to 200-300 cells/min) and adhesion (2 to 15-20 cells/100 microm), and a very dramatic increase in emigration ( approximately 1 to >40 cells/field) was observed over 24 h. Although rolling and adhesion was dramatically blunted in P-selectin- or P selectin/ICAM-1-deficient mice, emigrated cell number was similar to that observed in wild-type mice. Leukocyte rolling, adhesion and emigration was almost entirely abrogated over 24 h in E/P-selectin-deficient mice, demonstrating that antigen-induced leukocyte recruitment can be entirely disrupted in the absence of both endothelial selectins. However, E/P-selectin-deficient mice were able to recruit leukocytes at 24 h after TNF-alpha challenge. Rolling 24 h post-TNF-alpha in E/P-selectin-deficient mice was not inhibitable with anti-L-selectin antibody, suggesting an entirely selectin-independent pathway of rolling. We identified this pathway to be alpha (4)-integrin dependent and demonstrated that VCAM-1 expression was increased only in mice challenged with TNF-alpha. These data demonstrate that, in vivo, sufficient amounts of TNF-alpha can recruit leukocytes independently of selectins, whereas inhibition of endothelial selectins is the optimal intervention in reducing the immune response to antigen.
McCafferty
D M
DM
Immunology Research Group, Department of Medical Physiology, University of Calgary, Calgary, Canada.
Kanwar
S
S
Granger
D N
DN
Kubes
P
P
D000818:Animals; D002465:Cell Movement; D019040:E-Selectin / Q000032:analysis / Q000502:physiology*; D006439:Hemodynamics; D007114:Immunization; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010047:Ovalbumin / Q000276:immunology; D019007:P-Selectin / Q000032:analysis / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
D019040:E-Selectin; D019007:P-Selectin; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D010047:Ovalbumin