L-selectin shedding regulates leukocyte recruitment

A Hafezi-Moghadam, KL Thomas, AJ Prorock… - The Journal of …, 2001 - rupress.org
A Hafezi-Moghadam, KL Thomas, AJ Prorock, Y Huo, K Ley
The Journal of experimental medicine, 2001rupress.org
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 …
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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