Chemoattractants Induce a Rapid and Transient Upregulation of Monocyte α4 Integrin Affinity for Vascular Cell Adhesion Molecule 1 Which Mediates Arrest

Chan, Jason R.; Hyduk, Sharon J.; Cybulsky, Myron I.

doi:10.1084/jem.193.10.1149

Cited by 148 publications

(148 citation statements)

References 61 publications

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“…Most strikingly, it appeared that immobilized SDF-1␣ acted rapidly, on the order of 200 ms, to convert transient tethering interactions to rolling followed by firm adhesion. The blocking effects of the small molecule as well as the parallel effect of G protein-coupled receptor inhibition strongly implicated SDF-1␣ induction of high-affinity VLA-4 as critical for the arrest of PBL, consistent with observations of fMLP-stimulated monocytes under flow conditions (38). SDF-1␣ effects, although rapid, were secondary to the initial VLA-4 tethering event as both low-and high-affinity states of VLA-4 equivalently supported tethering.…”

Section: Discussionsupporting

confidence: 62%

Immobilized Stromal Cell-Derived Factor-1α Triggers Rapid VLA-4 Affinity Increases to Stabilize Lymphocyte Tethers on VCAM-1 and Subsequently Initiate Firm Adhesion

DiVietro

Brown

Sklar

et al. 2007

The Journal of Immunology

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The integrin VLA-4 (α4β1) mediates tethering and rolling events as well as firm adhesion of leukocytes to VCAM-1. Unlike selectins, VLA-4 integrin-mediated lymphocyte adhesiveness can be modulated by chemokines through intracellular signaling pathways. To investigate the effects of the chemokine stromal cell-derived factor-1α (SDF-1α) on VLA-4-mediated lymphocyte adhesion, human PBL were flowed over VCAM-1 substrates in a parallel plate flow chamber with surface-immobilized SDF-1α, a potent activator of firm adhesion. The initial tethering interactions had a median lifetime of 200 ms, consistent with the half-life of low-affinity VLA-4-VCAM-1 bonds. Immobilized SDF-1α acted within the lifetime of a primary tether to stabilize initial tethering interactions, increasing the likelihood a PBL would remain interacting with the surface. As expected, the immobilized SDF-1α also increased the ratio of PBL firm adhesion to rolling. An LDV peptide-based small molecule that preferentially binds high-affinity VLA-4 reduced PBL firm adhesion to VCAM-1 by 90%. The reduction in firm adhesion due to blockage of high-affinity VLA-4 was paralleled by a 4-fold increase in the fraction of rolling PBL. Chemokine activation of PBL firm adhesion on VCAM-1 depended on induction of high-affinity VLA-4 rather than recruitment of a pre-existing pool of high-affinity VLA-4 as previously thought.

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Section: Discussionsupporting

confidence: 62%

Immobilized Stromal Cell-Derived Factor-1α Triggers Rapid VLA-4 Affinity Increases to Stabilize Lymphocyte Tethers on VCAM-1 and Subsequently Initiate Firm Adhesion

DiVietro

Brown

Sklar

et al. 2007

The Journal of Immunology

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“…Indeed, expression of α4 in CHO cells promotes protrusion of broad lamellipodia in response to scratch wounding (36). Furthermore, phosphorylated α4 integrin preferentially localizes to the leading edge of migrating cells and this localization is linked to positive regulation of lamellipodial extensions and enhanced cell migration (37,38). Unexpectedly, we found that Abi1 interacts with the purified α4 cytoplasmic tail and colocalizes with the endogenous phosphorylated α4 integrin at the leading edge of spreading cells.…”

Section: Discussionmentioning

confidence: 74%

Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the α4 integrin

Ring

Ginsberg

Haling

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Dynamic signals linking the actin cytoskeleton and cell adhesion receptors are essential for morphogenesis during development and normal tissue homeostasis. Abi1 is a central regulator of actin polymerization through interactions with multiple protein complexes. However, the in vivo role of Abi1 remains to be defined. The α4 integrin adhesion receptor is associated with enhanced protrusive activity and regulation of directional cell migration. Among integrin subunits, α4 exhibits unique properties in that it predominantly accumulates at the leading edge of migrating cells; however, the pathways that link the actin-regulatory machinery to α4 at the leading edge have remained elusive. We generated Abi1 KO mice and found that loss of Abi1 phenocopies KO of α4. Mice lacking Abi1 or α4 exhibit midgestational lethality with abnormalities in placental and cardiovascular development. Notably, purified Abi1 protein binds directly to the α4 cytoplasmic tail and endogenous Abi1 colocalizes with phosphorylated α4 at the leading edge of spreading cells. Moreover, Abi1-deficient cells expressing α4 have impaired cell spreading, which is rescued by WT Abi1 but not an Abi1 mutant lacking the α4-binding site. These data reveal a direct link between the α4 integrin and actin polymerization and uncover a role for Abi1 in the regulation of morphogenesis in vivo. The Abi1–α4 interaction establishes a mechanistic paradigm for signaling between adhesion events and enhanced actin polymerization at the earliest stages of protrusion.

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“…T-cell detachment assay. Shear-mediated detachment assays were performed to determine changes in T-cell integrin affinity and avidity necessary for T-cell firm adhesion (25). Briefly, NOD/LtJ T-cells were introduced into the flow chamber and allowed to adhere to endothelial monolayers for 15 min under static conditions.…”

Section: Methodsmentioning

confidence: 99%

Stromal Cell–Derived Factor-1/CXCL12 Stimulates Chemorepulsion of NOD/LtJ T-Cell Adhesion to Islet Microvascular Endothelium

et al. 2008

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OBJECTIVE—Diabetogenic T-cell recruitment into pancreatic islets faciltates β-cell destruction during autoimmune diabetes, yet specific mechanisms governing this process are poorly understood. The chemokine stromal cell–derived factor-1 (SDF-1) controls T-cell recruitment, and genetic polymorphisms of SDF-1 are associated with early development of type 1 diabetes. RESEARCH DESIGN AND METHODS—Here, we examined the role of SDF-1 regulation of diabetogenic T-cell adhesion to islet microvascular endothelium. Islet microvascular endothelial cell monolayers were activated with tumor necrosis factor-α (TNF-α), subsequently coated with varying concentrations of SDF-1 (1–100 ng/ml), and assayed for T-cell/endothelial cell interactions under physiological flow conditions. RESULTS—TNF-α significantly increased NOD/LtJ T-cell adhesion, which was completely blocked by SDF-1 in a dose-dependent manner, revealing a novel chemorepulsive effect. Conversely, SDF-1 enhanced C57BL/6J T-cell adhesion to TNF-α–activated islet endothelium, demonstrating that SDF-1 augments normal T-cell adhesion. SDF-1 chemorepulsion of NOD/LtJ T-cell adhesion was completely reversed by blocking Giα-protein–coupled receptor activity with pertussis toxin. CXCR4 protein expression was significantly decreased in NOD/LtJ T-cells, and inhibition of CXCR4 activity significantly reversed SDF-1 chemorepulsive effects. Interestingly, SDF-1 treatment significantly abolished T-cell resistance to shear-mediated detachment without altering adhesion molecule expression, thus demonstrating decreased integrin affinity and avidity. CONCLUSIONS—In this study, we have identified a previously unknown novel function of SDF-1 in negatively regulating NOD/LtJ diabetogenic T-cell adhesion, which may be important in regulating diabetogenic T-cell recruitment into islets.

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Chemoattractants Induce a Rapid and Transient Upregulation of Monocyte α4 Integrin Affinity for Vascular Cell Adhesion Molecule 1 Which Mediates Arrest

Cited by 148 publications

References 61 publications

Immobilized Stromal Cell-Derived Factor-1α Triggers Rapid VLA-4 Affinity Increases to Stabilize Lymphocyte Tethers on VCAM-1 and Subsequently Initiate Firm Adhesion

Immobilized Stromal Cell-Derived Factor-1α Triggers Rapid VLA-4 Affinity Increases to Stabilize Lymphocyte Tethers on VCAM-1 and Subsequently Initiate Firm Adhesion

Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the α4 integrin

Stromal Cell–Derived Factor-1/CXCL12 Stimulates Chemorepulsion of NOD/LtJ T-Cell Adhesion to Islet Microvascular Endothelium

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