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
,
Kennard L. Thomas
,
Alyson J. Prorock
,
Yuqing Huo
,
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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