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A down-regulatable E-selectin ligand is functionally important for PSGL-1-independent leukocyte-endothelial cell
Renata C O Zanardo1, Claudine S Bonder, John M Hwang
1Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1.
Blood
|August 12, 2004
Summary
P-selectin glycoprotein-1 (PSGL-1) mediates P-selectin rolling but E-selectin rolling is partly PSGL-1-independent. This PSGL-1-independent E-selectin rolling can be downregulated and still drive inflammation.
Area of Science:
- Immunology
- Cellular Biology
- Vascular Biology
Background:
- P-selectin glycoprotein-1 (PSGL-1) is crucial for P-selectin-mediated cell adhesion.
- The role of PSGL-1 in E-selectin-dependent cell rolling remains controversial.
Purpose of the Study:
- To investigate the relative contributions of PSGL-1-dependent and -independent mechanisms in E-selectin-mediated cell rolling.
- To determine the physiological relevance of PSGL-1-independent E-selectin rolling in inflammatory responses.
Main Methods:
- Utilized PSGL-1 knockout mice and blocking antibodies against PSGL-1.
- Assessed cell rolling in cremaster microcirculation and in vitro binding assays.
- Employed a P- and E-selectin-dependent cutaneous contact hypersensitivity model.
Main Results:
- PSGL-1 deficiency or blockade abolished P-selectin rolling but only partially inhibited E-selectin rolling.
- A PSGL-1-independent E-selectin ligand was identified on neutrophils, down-regulated by systemic but not local TNF-alpha activation.
- Despite reduced E-selectin ligand expression, PSGL-1-independent rolling was sufficient to induce significant contact hypersensitivity.
Conclusions:
- E-selectin mediates both PSGL-1-dependent and -independent cell rolling.
- The PSGL-1-independent pathway is physiologically relevant and can compensate for PSGL-1 function in inflammation.
- Systemic activation can down-regulate this independent ligand, impacting inflammatory cell recruitment.