Abstract
Neutrophil recruitment during acute inflammation is triggered by G-protein-linked chemotactic receptors that in turn activate β2 integrin (CD18), deemed a critical step in facilitating cell capture and arrest under the shear force of blood flow. A conformational switch in the I domain allosteric site (IDAS) and in CD18 regulates LFA-1 affinity for endothelial ligands including intercel. lular adhesion molecule 1 (ICAM-1). We examined the dynamics of CD18 activation in terms of the efficiency of neutrophil capture of ICAM-1, and we correlated this with the membrane topography of 327C, an antibody that recognizes the active conformation of CD18 I-like domain. Adhesion increased in direct proportion to chemotactic stimulus rising 7-fold over a log range of interleukin-8 (IL-8). A threshold dose of ∼75 pM IL-8, corresponding to ligation of only ∼10-100 receptors, was sufficient to activate ∼20,000 CD18 and a rapid boost in the capture efficiency on ICAM-1. This was accompanied by a rapid redistribution of active LFA-1, but not Mac-1, into membrane patches, a necessary component for optimum adhesion efficiency. Shear-resistant arrest on a monolayer of ICAM-1 was reversed within minutes of chemotactic stimulation correlating with a shift from high to low affinity CD18 and dispersal of patches of active CD18. Mobility of active CD18 into high avidity patches was dependent on phosphatidylinositol 3-kinase activity and not F-actin polymerization. The data reveal that the number of chemotactic receptors bound and the topography and lifetime of high affinity LFA-1 tightly regulate the efficiency of neutrophil capture on ICAM-1.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 20660-20670 |
| Number of pages | 11 |
| Journal | Journal of Biological Chemistry |
| Volume | 277 |
| Issue number | 23 |
| DOIs | |
| State | Published - Jun 7 2002 |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Dynamic regulation of LFA-1 activation and neutrophil arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow. / Lum, Aaron F H; Green, Chad E.; Lee, Garrett R.; Staunton, Donald E.; Simon, Scott I.
In: Journal of Biological Chemistry, Vol. 277, No. 23, 07.06.2002, p. 20660-20670.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dynamic regulation of LFA-1 activation and neutrophil arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow
AU - Lum, Aaron F H
AU - Green, Chad E.
AU - Lee, Garrett R.
AU - Staunton, Donald E.
AU - Simon, Scott I.
PY - 2002/6/7
Y1 - 2002/6/7
N2 - Neutrophil recruitment during acute inflammation is triggered by G-protein-linked chemotactic receptors that in turn activate β2 integrin (CD18), deemed a critical step in facilitating cell capture and arrest under the shear force of blood flow. A conformational switch in the I domain allosteric site (IDAS) and in CD18 regulates LFA-1 affinity for endothelial ligands including intercel. lular adhesion molecule 1 (ICAM-1). We examined the dynamics of CD18 activation in terms of the efficiency of neutrophil capture of ICAM-1, and we correlated this with the membrane topography of 327C, an antibody that recognizes the active conformation of CD18 I-like domain. Adhesion increased in direct proportion to chemotactic stimulus rising 7-fold over a log range of interleukin-8 (IL-8). A threshold dose of ∼75 pM IL-8, corresponding to ligation of only ∼10-100 receptors, was sufficient to activate ∼20,000 CD18 and a rapid boost in the capture efficiency on ICAM-1. This was accompanied by a rapid redistribution of active LFA-1, but not Mac-1, into membrane patches, a necessary component for optimum adhesion efficiency. Shear-resistant arrest on a monolayer of ICAM-1 was reversed within minutes of chemotactic stimulation correlating with a shift from high to low affinity CD18 and dispersal of patches of active CD18. Mobility of active CD18 into high avidity patches was dependent on phosphatidylinositol 3-kinase activity and not F-actin polymerization. The data reveal that the number of chemotactic receptors bound and the topography and lifetime of high affinity LFA-1 tightly regulate the efficiency of neutrophil capture on ICAM-1.
AB - Neutrophil recruitment during acute inflammation is triggered by G-protein-linked chemotactic receptors that in turn activate β2 integrin (CD18), deemed a critical step in facilitating cell capture and arrest under the shear force of blood flow. A conformational switch in the I domain allosteric site (IDAS) and in CD18 regulates LFA-1 affinity for endothelial ligands including intercel. lular adhesion molecule 1 (ICAM-1). We examined the dynamics of CD18 activation in terms of the efficiency of neutrophil capture of ICAM-1, and we correlated this with the membrane topography of 327C, an antibody that recognizes the active conformation of CD18 I-like domain. Adhesion increased in direct proportion to chemotactic stimulus rising 7-fold over a log range of interleukin-8 (IL-8). A threshold dose of ∼75 pM IL-8, corresponding to ligation of only ∼10-100 receptors, was sufficient to activate ∼20,000 CD18 and a rapid boost in the capture efficiency on ICAM-1. This was accompanied by a rapid redistribution of active LFA-1, but not Mac-1, into membrane patches, a necessary component for optimum adhesion efficiency. Shear-resistant arrest on a monolayer of ICAM-1 was reversed within minutes of chemotactic stimulation correlating with a shift from high to low affinity CD18 and dispersal of patches of active CD18. Mobility of active CD18 into high avidity patches was dependent on phosphatidylinositol 3-kinase activity and not F-actin polymerization. The data reveal that the number of chemotactic receptors bound and the topography and lifetime of high affinity LFA-1 tightly regulate the efficiency of neutrophil capture on ICAM-1.
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UR - http://www.scopus.com/inward/citedby.url?scp=0037036421&partnerID=8YFLogxK
U2 - 10.1074/jbc.M202223200
DO - 10.1074/jbc.M202223200
M3 - Article
C2 - 11929876
AN - SCOPUS:0037036421
VL - 277
SP - 20660
EP - 20670
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 23
ER -