Transmigration of neutrophils across inflamed endothelium is signaled through LFA-1 and Src family kinase

Melissa R. Sarantos, Hong Zhang, Ulrich Y. Schaff, Neha Dixit, Heather N. Hayenga, Clifford A. Lowell, Scott I. Simon

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Leukocyte capture on inflamed endothelium is facilitated by a shift in LFA-1 from low to high affinity that supports binding to ICAM-1. LFA-1 bonds help anchor polymorphonuclear leukocytes (PMN) to inflamed endothelium in shear flow, and their redistribution to the leading edge guides pseudopod formation, migration, and extravasation. These events can be disrupted at the plasma membrane by stabilizing LFA-1 in a low- or intermediate-affinity state with allosteric small molecules. We hypothesized that a minimum dimeric bond formation between high-affinity LFA-1 and ICAM-1 under shear stress is necessary to catalyze transmembrane signaling of directed cell migration. Microspheres and substrates were derivatized with monomeric or dimeric ICAM-1 to simulate the surface of inflamed endothelium under defined ligand valence. Binding to dimeric ICAM-1, and not monomeric ICAM-1, was sufficient to elicit assembly of F-actin and phosphorylation of Src family kinases that colocalized with LFA-1 on adherent PMN. Genetic deletion or small molecule inhibition of Src family kinases disrupted their association with LFA-1 that correlated with diminished polarization of arrested PMN and abrogation of transmigration on inflamed endothelium. We conclude that dimeric bond clusters of LFA-1/ICAM-1 provide a key outside-in signal for orienting cytoskeletal dynamics that direct PMN extravasation at sites of inflammation.

Original languageEnglish (US)
Pages (from-to)8660-8669
Number of pages10
JournalJournal of Immunology
Volume181
Issue number12
StatePublished - Dec 15 2008

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ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Sarantos, M. R., Zhang, H., Schaff, U. Y., Dixit, N., Hayenga, H. N., Lowell, C. A., & Simon, S. I. (2008). Transmigration of neutrophils across inflamed endothelium is signaled through LFA-1 and Src family kinase. Journal of Immunology, 181(12), 8660-8669.