Transit time of leukocytes rolling through venules controls cytokine-induced inflammatory cell recruitment in vivo.

Jung, Unsu; Norman, Keith E.; Scharffetter‐­Kochanek, Karin; Beaudet, Arthur L.; Ley, Klaus

doi:10.1172/jci119893

Cited by 245 publications

(239 citation statements)

References 41 publications

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“…This allows more opportunity for endothelial cell chemokines to activate neutrophil ␤2 integrins to a high-affinity conformation, which causes neutrophils to arrest. 53,54 Clustering of E-selectin may be essential for neutrophils to roll sufficiently slowly so that chemokines can signal. Furthermore, interactions of E-selectin with neutrophil PSGL-1 signal activation of ␤2 integrins to a low affinity but extended conformation that further slows rolling.…”

Section: Discussionmentioning

confidence: 99%

Clustering endothelial E-selectin in clathrin-coated pits and lipid rafts enhances leukocyte adhesion under flow

Setiadi

McEver

2008

Blood

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During inflammation, E-selectin expressed on cytokine-activated endothelial cells mediates leukocyte rolling under flow. E-selectin undergoes endocytosis and may associate with lipid rafts. We asked whether distribution of E-selectin in membrane domains affects its functions. E-selectin was internalized in transfected CHO cells or cytokine-activated human umbilical vein endothelial cells (HUVECs). Confocal microscopy demonstrated colocalization of E-selectin with ␣-adaptin, a clathrin-associated protein.Deleting the cytoplasmic domain of Eselectin or disrupting clathrin-coated pits with hypertonic medium blocked internalization of E-selectin, reduced colocalization of E-selectin with ␣-adaptin, and inhibited E-selectin-mediated neutrophil rolling under flow. Unlike CHO cells, HUVECs expressed a small percentage of E-selectin in lipid rafts. Even fewer neutrophils rolled on E-selectin in HUVECs treated with hypertonic medium and with methyl-␤-cyclodextrin, which disrupts lipid rafts. These data demonstrate that E-selectin clusters in both clathrin-coated pits and lipid rafts of endothelial cells but is internalized in clathrin-coated pits. Distribution in both domains markedly enhances E-selectin's ability to mediate leukocyte rolling under flow. IntroductionRecruitment of leukocytes into secondary lymphoid organs or inflamed tissues requires that the cells first tether to and roll on vascular surfaces. Interactions of selectins with their glycoconjugate ligands mediate tethering and rolling, 1 which precedes integrindependent deceleration, arrest, and transmigration of leukocytes across the endothelial cell layer. 2 L-selectin, expressed on leukocytes, binds to ligands on other leukocytes and on endothelial cells in lymph nodes and in some regions of inflammation. P-and E-selectin, expressed on activated platelets or endothelial cells, bind to ligands on leukocytes. The leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1) is the dominant ligand for P-and L-selectin and an important ligand for E-selectin. 3,4 The manner in which selectins or their ligands distribute on cell surfaces has major influence on rolling behavior. 5 For example, L-selectin and PSGL-1 are located on tips of microvilli, 6,7 which enhances the initial tethering of leukocytes. 8 The extended length of P-selectin helps capture flowing neutrophils and slow their rolling velocities, presumably by increasing encounters with PSGL-1. 9 The dimeric structures of P-selectin and PSGL-1 allow them to form dimeric bonds that prolong tether duration and strength. 10 Membrane anchorage of L-selectin and P-selectin through binding of their cytoplasmic domains to cytosolic proteins favors rolling. L-selectin anchors through interactions of its cytoplasmic domain with the cytoskeleton to effectively engage its ligands under flow. 11 P-selectin uses a different mechanism to cluster on the cell surface. Thrombin or histamine mobilizes P-selectin from the membranes of Weibel-Palade bodies to the plasma membranes of endothelial cells. 12,13 Sequences in t...

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Section: Discussionmentioning

confidence: 99%

Clustering endothelial E-selectin in clathrin-coated pits and lipid rafts enhances leukocyte adhesion under flow

Setiadi

McEver

2008

Blood

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“…When cells roll more slowly, they have more time to be further activated by chemokines secreted or presented by the endothelium and to become firmly attached (50). We have previously shown that naive cells do not adhere to normal retinal vessels and that only very few activated T cells (5-10 cells/retina/30 min) adhere to normal retinal vessels (51).…”

Section: Trafficking Of Polarized Cells In Mouse Retinamentioning

confidence: 99%

Recruitment of IFN-γ-Producing (Th1-Like) Cells into the Inflamed Retina In Vivo Is Preferentially Regulated by P-Selectin Glycoprotein Ligand 1:P/E-Selectin Interactions

Manivannan

Jiang

et al. 2004

The Journal of Immunology

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Although there is evidence that altering the Th1/Th2 balance toward Th2 cells may be important in the resolution of Th1-type autoimmune disease, adoptive transfer of Th2 cells is not effective in protecting against Th1-type disease and may cause disease. Therefore, we examined the recruitment of Th1- and Th2-like cells into the retina in the murine autoimmune disease experimental autoimmune uveoretinitis. CD4 T cells were polarized in vitro to IFN-γ-producing Th1-like cells and non-IFN-γ-producing Th2-like cells, labeled, and adoptively transferred. Trafficking to the retina in vivo was evaluated by scanning laser ophthalmoscopy and infiltration by confocal microscopy. There were more rolling and adherent Th1-like cells and they rolled more slowly than did Th2-like cells. Th1-like cells were preferentially recruited into the retinal parenchyma at both initiation and resolution. Surface P-selectin glycoprotein ligand 1 (PSGL-1) and LFA-1 were up-regulated on both populations but were expressed at higher levels on Th1-like cells. Up-regulation of CD44 expression was higher on Th2-like cells. P-selectin, E-selectin, and ICAM-1 are up-regulated on postcapillary venules in the retina. Pretreatment of Th1-like cells with anti-PSGL-1 inhibited rolling and infiltration of Th1-like cells but not Th2-like cells, providing direct in vivo evidence for the inability of Th2 to respond to P/E-selectin despite increased expression of PSGL-1. Anti-LFA-1 pretreatment inhibited infiltration of both Th1- and Th2-like cells, but more so Th-1. We suggest that random trafficking of activated T cells (both Th1 and Th2) across the blood-retina barrier is mediated by CD44:CD44R and LFA-1:ICAM-1, whereas preferential recruitment of Th1 cells is mediated by PSGL-1:P/E-selectin.

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“…The initial step of recruitment is leukocyte capture and rolling along the endothelial surface of postcapillary venules, which permits firm leukocyte adhesion in the face of high shear rates and eventual transmigration through the vessel wall (1,2). By virtue of slowing leukocyte transit through regions of inflammation, rolling may also enhance leukocyte exposure to proinflammatory cytokines and chemoattractants (3,4). The process of leukocyte rolling is mediated primarily by the selectin family of adhesion molecules that share common structural features, including a similar NH 2 -terminal lectin domain (5).…”

mentioning

confidence: 99%

“…Thrombin induces P-selectin expression by a cascade of events initiated by binding to the thrombin receptor, or proteaseactivated receptor-1 (PAR1), 4 on the endothelial cell surface (13). This receptor belongs to a family of unique G protein-coupled receptors that undergo proteolytic cleavage of the amino-terminal exodomain by serine proteases to produce a new amino terminus that functions as a tethered ligand to activate receptor function (14,15).…”

mentioning

confidence: 99%

Delayed Onset of Inflammation in Protease-Activated Receptor-2-Deficient Mice

Lindner

Kahn

Coughlin

et al. 2000

The Journal of Immunology

252

209

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Endothelial surface expression of P-selectin and subsequent leukocyte rolling in venules can be induced by mast cell-derived histamine and binding of thrombin to protease-activated receptor-1 (PAR1). We hypothesized that activation of endothelial PAR2 by mast cell tryptase or other proteases also contributes to inflammatory responses. Leukocyte rolling flux and rolling velocity were assessed by intravital microscopy of the cremaster muscles of wild-type mice following perivenular micropipette injections of a control (LSIGRL) or PAR2-activating (SLIGRL) oligopeptide. Injection of SLIGRL increased mean rolling leukocyte flux fraction from 34 ± 11 to 71 ± 24% (p < 0.05) and decreased mean rolling velocity from 63 ± 29 to 32 ± 2 μm/s (p < 0.05). No significant changes occurred with control peptide injection. To further evaluate the role of PAR2 in inflammatory responses, PAR2-deficient mice were generated by gene targeting and homologous recombination. Perivenular injections of SLIGRL resulted in only a small increase in rolling leukocyte flux fraction (from 21 ± 8 to 30 ± 2%) and no change in rolling velocity. Leukocyte rolling after surgical trauma was assessed in 9 PAR2-deficient and 12 wild-type mice. Early (0–15 min) after surgical trauma, the mean leukocyte rolling flux fraction was lower (10 ± 3 vs 30 ± 6%, p < 0.05) and mean rolling velocity was higher (67 ± 46 vs 52 ± 36 μm/s, p < 0.01) in PAR2-deficient compared with control mice. The defect in leukocyte rolling in PAR2-deficient mice did not persist past 30 min following surgical trauma. These results indicate that activation of PAR2 produces microvascular inflammation by rapid induction of P-selectin-mediated leukocyte rolling. In the absence of PAR2, the onset of inflammation is delayed.

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Transit time of leukocytes rolling through venules controls cytokine-induced inflammatory cell recruitment in vivo.

Cited by 245 publications

References 41 publications

Clustering endothelial E-selectin in clathrin-coated pits and lipid rafts enhances leukocyte adhesion under flow

Clustering endothelial E-selectin in clathrin-coated pits and lipid rafts enhances leukocyte adhesion under flow

Recruitment of IFN-γ-Producing (Th1-Like) Cells into the Inflamed Retina In Vivo Is Preferentially Regulated by P-Selectin Glycoprotein Ligand 1:P/E-Selectin Interactions

Delayed Onset of Inflammation in Protease-Activated Receptor-2-Deficient Mice

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