L-selectin shedding regulates leukocyte recruitment

The physiologic role of L-selectin shedding is unknown. Here, we investigat e the effect of L-selectin shedding on firm adhesion and transmigration. In a tumor necrosis factor alpha -induced model of inflammation, inhibition o f L-selectin shedding significantly increased firm adhesion and transmigrat ion by a lymphocyte function-associated antigen (LFA)-1 and intercellular a dhesion molecule (ICAM)-1-dependent mechanism, We examined thr quality of l eukocyte rolling and L-selectin-mediated signaling. Blockade of L-selectin shedding significantly reduced the "jerkiness" of leukocyte rolling, define d as the variability of velocity over time. A low level of jerkiness was al so observed in the rolling of microbeads conjugated with L-selectin, a mode l system lacking the mechanism for L-selectin shedding. Inhibition of L-sel ectin shedding potentiated activation of LFA-1 and Mac-1 induced by L-selec tin 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 leukocyt e exposure to the inflamed endothelium by decreasing jerkiness and (b) prom oting leukocyte activation by outside-in signaling. These observations help to resolve the apparent discrepancy between the minor contribution of L-se lectin to rolling and the significant leukocyte recruitment defect in L-sel ectin knockout mice.