The physiologic role of L-selectin shedding is unknown. Here, we investigate the effect of L-selectin shedding on firm adhesion and transmigration. In a tumor necrosis factor α–induced model of inflammation, inhibition of L-selectin shedding significantly increased firm adhesion and transmigration by a lymphocyte function–associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1–dependent mechanism. We examined the quality of leukocyte rolling and L-selectin–mediated signaling. Blockade of L-selectin shedding significantly reduced the “jerkiness” of leukocyte rolling, defined as the variability of velocity over time. A low level of jerkiness was also observed in the rolling of microbeads conjugated with L-selectin, a model system lacking the mechanism for L-selectin shedding. Inhibition of L-selectin shedding potentiated activation of LFA-1 and Mac-1 induced by L-selectin cross-linking as shown by activation epitope expression and binding of ICAM-1–conjugated beads. We conclude that inhibition of L-selectin shedding increases leukocyte adhesion and transmigration by (a) increasing leukocyte exposure to the inflamed endothelium by decreasing jerkiness and (b) promoting leukocyte activation by outside-in signaling. These observations help to resolve the apparent discrepancy between the minor contribution of L-selectin to rolling and the significant leukocyte recruitment defect in L-selectin knockout mice.
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2 April 2001
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April 02 2001
L-Selectin Shedding Regulates Leukocyte Recruitment
Ali Hafezi-Moghadam,
Ali Hafezi-Moghadam
aDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
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Kennard L. Thomas,
Kennard L. Thomas
aDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
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Alyson J. Prorock,
Alyson J. Prorock
aDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
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Yuqing Huo,
Yuqing Huo
aDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
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Klaus Ley
Klaus Ley
aDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
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Ali Hafezi-Moghadam
aDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
Kennard L. Thomas
aDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
Alyson J. Prorock
aDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
Yuqing Huo
aDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
Klaus Ley
aDepartment of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
Abbreviations used in this paper: GAM, goat anti–mouse; GAR, goat anti–rat; ICAM, intercellular adhesion molecule; wt, wild-type.
Received:
June 12 2000
Revision Requested:
February 06 2001
Accepted:
February 13 2001
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 2001 The Rockefeller University Press
2001
The Rockefeller University Press
J Exp Med (2001) 193 (7): 863–872.
Article history
Received:
June 12 2000
Revision Requested:
February 06 2001
Accepted:
February 13 2001
Citation
Ali Hafezi-Moghadam, Kennard L. Thomas, Alyson J. Prorock, Yuqing Huo, Klaus Ley; L-Selectin Shedding Regulates Leukocyte Recruitment. J Exp Med 2 April 2001; 193 (7): 863–872. doi: https://doi.org/10.1084/jem.193.7.863
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