The association between alpha4-integrin, P-selectin, and E-selectin in an allergic model of inflammation.
In this study, we examined the relationship between the endothelial selectins (P-selectin and E-selectin) and whether they are critical for alpha4-integrin-dependent leukocyte recruitment in inflamed (late phase response), cremasteric postcapillary venules. Animals were systemically sensitized and 2 wk later challenged intrascrotally with chicken ovalbumin. Leukocyte rolling flux, adhesion, and emigration were assessed at baseline and 4 and 8 h postantigen challenge. There was a significant increase in leukocyte rolling flux, adhesion, and emigration in sensitized and challenged mice at both 4 and 8 h. At 8 h, the increase in leukocyte rolling flux was approximately 50% inhibitable by an anti-alpha4-integrin antibody, 98% inhibitable by fucoidin (a selectin-binding carbohydrate), and 100% inhibitable by an anti-P-selectin antibody. P-selectin-deficient animals displayed no leukocyte rolling or adhesion at 8 h after challenge. However, at 8 h there were many emigrated leukocytes in the perivascular space suggesting P-selectin-independent rolling at an earlier time point. Indeed, at 4 h postantigen challenge in P-selectin-deficient mice, there was increased leukocyte rolling, adhesion, and emigration. The rolling in the P-selectin-deficient mice at 4 h was largely alpha4-integrin dependent. However, there was an essential E-selectin-dependent component inasmuch as an anti-E-selectin antibody completely reversed the rolling, and in E-selectin and P-selectin double deficient mice rolling, adhesion and emigration were completely absent. These results illustrate that P-selectin underlies all of the antigen-induced rolling with a brief transient contribution from E-selectin in the P-selectin-deficient animals. Finally, the antigen-induced alpha4-integrin-mediated leukocyte recruitment is entirely dependent upon endothelial selectins.
Kanwar
S
S
Department of Medical Physiology, University of Calgary, Alberta, Canada.
Bullard
D C
DC
Hickey
M J
MJ
Smith
C W
CW
Beaudet
A L
AL
Wolitzky
B A
BA
Kubes
P
P
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002448:Cell Adhesion; D002645:Chickens; D003433:Crosses, Genetic; D006969:Hypersensitivity, Immediate / Q000276:immunology* / Q000503:physiopathology; D007114:Immunization; D007249:Inflammation / Q000276:immunology* / Q000503:physiopathology; D039441:Integrin alpha4; D019041:L-Selectin / Q000235:genetics / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D019007:P-Selectin / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
D015703:Antigens, CD; D019007:P-Selectin; D019041:L-Selectin; D039441:Integrin alpha4; D010047:Ovalbumin