A down-regulatable E-selectin ligand is functionally important for PSGL-1-independent leukocyte-endothelial cell interactions.
P-selectin glycoprotein-1 (PSGL-1) supports P-selectin-dependent rolling in vivo and in vitro. However, controversy exists regarding the importance of PSGL-1-dependent and -independent E-selectin rolling. Using antibodies against PSGL-1 and PSGL-1(-/-) mice, we demonstrated abolition of P-selectin-dependent rolling but only partial inhibition of E-selectin-mediated rolling in the cremaster microcirculation following local administration of tumor necrosis factor alpha (TNF-alpha). In vitro studies demonstrated that binding of recombinant mouse E-selectin chimera to PSGL-1(-/-) neutrophils was dramatically decreased in mice treated systemically but not locally with TNF-alpha. Further, PSGL-1 blockade abolished E-selectin-dependent rolling in wild-type mice following systemic TNF-alpha administration but not local TNF-alpha administration. Together, these data support an E-selectin ligand present on PSGL-1(-/-) neutrophils that is down-regulatable upon systemic but not local activation. To determine whether the PSGL-1-independent E-selectin ligand was physiologically important, we used a P- and E-selectin-dependent cutaneous contact hypersensitivity model. Binding studies showed no E-selectin ligand down-regulation in this model. The few cells that rolled on E-selectin ligand following PSGL-1 antibody administration or in PSGL-1 deficiency were sufficient to induce profound contact hypersensitivity. In conclusion, E-selectin mediates PSGL-1-dependent and independent rolling and the latter can be down-regulated by systemic activation and can replace PSGL-1 to support the development of inflammation.
Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1.
Renata C O
RC
Zanardo
Claudine S
CS
Bonder
John M
JM
Hwang
Graciela
G
Andonegui
Lixin
L
Liu
Dietmar
D
Vestweber
Lori
L
Zbytnuik
Paul
P
Kubes
D000818:Animals; D002450:Cell Communication; D003877:Dermatitis, Contact / Q000209:etiology; D015536:Down-Regulation; D019040:E-Selectin / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology*; D005260:Female; D007249:Inflammation / Q000209:etiology; D036904:Leukocyte Rolling; D007962:Leukocytes / Q000737:chemistry / Q000502:physiology*; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D018715:Microscopy, Video; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D019040:E-Selectin; D008024:Ligands; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D014409:Tumor Necrosis Factor-alpha