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

64 Citations (Scopus)

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

Fingerprint

Lymphocyte Function-Associated Antigen-1
Endothelium
Neutrophils
Integrins
Adhesion
Polarization
Selectins
Intercellular Adhesion Molecule-1
GTP-Binding Proteins
Pseudopodia
Vascular Endothelium
Conformations
Cytokines
Leukocytes
Molecules
Inflammation

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

Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium. / Green, Chad E.; Schaff, Ulrich Y.; Sarantos, Melissa R.; Lum, Aaron F H; Staunton, Donald E.; Simon, Scott I.

In: Blood, Vol. 107, No. 5, 01.03.2006, p. 2101-2111.

Research output: Contribution to journalArticle

Green, CE, Schaff, UY, Sarantos, MR, Lum, AFH, Staunton, DE & Simon, SI 2006, 'Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium', Blood, vol. 107, no. 5, pp. 2101-2111. https://doi.org/10.1182/blood-2005-06-2303
Green, Chad E. ; Schaff, Ulrich Y. ; Sarantos, Melissa R. ; Lum, Aaron F H ; Staunton, Donald E. ; Simon, Scott I. / Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium. In: Blood. 2006 ; Vol. 107, No. 5. pp. 2101-2111.
@article{713a3473fc7c4c3bbdbf4005c05babde,
title = "Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium",
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.",
author = "Green, {Chad E.} and Schaff, {Ulrich Y.} and Sarantos, {Melissa R.} and Lum, {Aaron F H} and Staunton, {Donald E.} and Simon, {Scott I.}",
year = "2006",
month = "3",
day = "1",
doi = "10.1182/blood-2005-06-2303",
language = "English (US)",
volume = "107",
pages = "2101--2111",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "5",

}

TY - JOUR

T1 - Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium

AU - Green, Chad E.

AU - Schaff, Ulrich Y.

AU - Sarantos, Melissa R.

AU - Lum, Aaron F H

AU - Staunton, Donald E.

AU - Simon, Scott I.

PY - 2006/3/1

Y1 - 2006/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33344475249&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33344475249&partnerID=8YFLogxK

U2 - 10.1182/blood-2005-06-2303

DO - 10.1182/blood-2005-06-2303

M3 - Article

VL - 107

SP - 2101

EP - 2111

JO - Blood

JF - Blood

SN - 0006-4971

IS - 5

ER -