L-selectin shedding regulates leukocyte recruitment

Ali Hafezi-Moghadam, Kennard L. Thomas, Alyson J. Prorock, Yuqing Huo, Klaus Ley

168 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)863-872
Number of pages10
JournalJournal of Experimental Medicine
Volume193
Issue number7
DOIs
Publication statusPublished - Apr 2 2001
Externally publishedYes

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Keywords

  • ICAM-1
  • Inflammation
  • Rolling velocity
  • Signaling
  • Trafficking

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Hafezi-Moghadam, A., Thomas, K. L., Prorock, A. J., Huo, Y., & Ley, K. (2001). L-selectin shedding regulates leukocyte recruitment. Journal of Experimental Medicine, 193(7), 863-872. https://doi.org/10.1084/jem.193.7.863