The Journal of Experimental Medicine
CSHL 2010 Immunology Conference
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Published online 2 April 2001.
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© The Rockefeller University Press, 0022-1007/2001/4/863/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 7, April 2, 2001 863-872

Original Article

L-Selectin Shedding Regulates Leukocyte Recruitment

Ali Hafezi-Moghadama, Kennard L. Thomasa, Alyson J. Prorocka, Yuqing Huoa, and Klaus Leya

a Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908
The Center for Blood Research, Harvard Medical School, 800 Huntington Ave., Boston, MA 02115.617-278-3368617-278-3339

moghadam{at}cbr.med.harvard.edu

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 {alpha}–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.

Key Words: inflammation • signaling • trafficking • rolling velocity • ICAM-1

Abbreviations used in this paper: GAM, goat anti–mouse; GAR, goat anti–rat; ICAM, intercellular adhesion molecule; wt, wild-type.

© 2001 The Rockefeller University Press


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