Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium

Chad E. Green, Ulrich Y. Schaff, Melissa R. Sarantos, Aaron F H Lum, Donald E. Staunton, Scott I. Simon

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Polymorphonuclear leukocyte (PMN) recruitment to vascular endothelium during acute inflammation involves cooperation between selectins, G-proteins, and β2-integrins. LFA-1 (CD11a/CD18) affinity correlates with specific adhesion functions because a shift from low to intermediate affinity supports rolling on ICAM-1, whereas high affinity is associated with shear-resistant leukocyte arrest. We imaged PMN adhesion on cytokine-inflamed endothelium in a parallel-plate flow chamber to define the dynamics of β2-integrin function during recruitment and transmigration. After arrest on inflamed endothelium, high-affinity LFA-1 aligned along the uropod-pseudopod major axis, which was essential for efficient neutrophil polarization and subsequent transmigration. An allosteric small molecule inhibitor targeted to the I-domain stabilized LFA-1 in an intermediate-affinity conformation, which supported neutrophil rolling but inhibited cell polarization and abrogated transmigration. We conclude that a shift in LFA-1 from intermediate to high affinity during the transition from rolling to arrest provides the contact-mediated signaling and guidance necessary for PMN transmigration on inflamed endothelium.

Original languageEnglish (US)
Pages (from-to)2101-2111
Number of pages11
JournalBlood
Volume107
Issue number5
DOIs
StatePublished - Mar 1 2006

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ASJC Scopus subject areas

  • Hematology

Cite this

Green, C. E., Schaff, U. Y., Sarantos, M. R., Lum, A. F. H., Staunton, D. E., & Simon, S. I. (2006). Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium. Blood, 107(5), 2101-2111. https://doi.org/10.1182/blood-2005-06-2303