Abstract 171: Role of α-Actinin-4-Dependent Endothelial Cell Stiffness in Neutrophil Transmigration

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Peter Hordijk ◽  
Antje Schaefer ◽  
Joost te Riet ◽  
Katje Ritz ◽  
Mark Hoogenboezem ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Feedback Loop ◽  
Leukocyte Adhesion ◽  
Cell Stiffness ◽  
Intercellular Adhesion Molecule ◽  
Ageing Population ◽  
Intercellular Adhesion Molecule 1 ◽  
Endothelial Lining ◽  
Human Disorders

Inflammation is causally linked to many chronic human disorders and constitutes a growing problem in the ageing population. The inflammatory process is driven by interactions of activated leukocytes with the endothelial lining of blood vessels. This requires binding of leukocyte β2-integrins to endothelial ICAM-1 (InterCellular Adhesion Molecule-1), which allows leukocyte adhesion, spreading, crawling and transendothelial migration (TEM). Integrin binding induces ICAM-1 clustering and its consequent association to F-actin which enforces leukocyte adhesion. Here, we analyzed the molecular basis of this positive feedback loop. We show that ICAM-1 clustering promotes its binding to F-actin through distinct complexes with FilaminB, Cortactin and α-Actinin-4. We found that α-Actinin-4 regulates endothelial cell peripheral stiffness, which is sensed by adherent neutrophils and promotes adhesion, spreading, crawling and TEM. Conversely, increasing endothelial cell stiffness stimulates the ICAM-1-α-Actinin-4 interaction. Finally, we found that the endothelial lining of atherosclerotic plaques, which is characterized by increased stiffness and leukocyte infiltration, shows increased expression of α-Actinin-4. These results identify α-Actinin-4-regulated endothelial cell stiffness as a novel pro-inflammatory event that promotes ICAM-1-mediated leukocyte adhesion and TEM.

scholarly journals Effects of plasma from hibernating ground squirrels on monocyte-endothelial cell adhesive interactions

1997 ◽  
Vol 273 (6) ◽  
pp. R1861-R1869 ◽  
Author(s):  
Yoshihide Yasuma ◽  
Richard M. McCarron ◽  
Maria Spatz ◽  
John M. Hallenbeck
Keyword(s):  
Leukocyte Adhesion ◽  
Ground Squirrels ◽  
Intercellular Adhesion Molecule ◽  
Monocyte Adhesion ◽  
Intercellular Adhesion Molecule 1 ◽  
Inflammatory Mechanism ◽  
Ischemic Tissue ◽  
Adhesive Interactions ◽  
Natural Tolerance

Adhesion and subsequent penetration of leukocytes into central nervous system ischemic tissue proceeds via a coordinated inflammatory mechanism involving adhesion molecules at the blood-endothelium interface. Mammalian hibernation is a state of natural tolerance to severely reduced blood flow-oxygen delivery (i.e., ischemia). Hibernating thirteen-lined ground squirrels were investigated in an attempt to identify factors responsible for regulating this tolerance. Since leukocytopenia is closely associated with entrance into hibernation, the role of leukocyte adhesion to endothelium in this phenomenon was examined. Intercellular adhesion molecule-1 (ICAM-1) is expressed by endothelium and regulates interactions with circulating leukocytes that may result in margination or extravasation. ICAM-1 expression by rat cerebral microvascular endothelial cells (EC) cultured with plasma from hibernating (HP) or nonhibernating (NHP) thirteen-lined ground squirrels was dose dependently increased by HP and, to a lesser extent, by NHP. Treatment of EC with HP coincidentally induced significantly greater increases in monocyte adhesion to EC (37.2%) than were observed with NHP (23.9%). Study of the effects of HP and NHP on monocyte adhesion to EC may identify mechanisms responsible for ischemic tolerance in hibernators and could lead to the development of novel therapeutic approaches to the treatment of stroke.

Role of ICAM-1 in chronic hepatic allograft rejection in the rat

2002 ◽  
Vol 283 (1) ◽  
pp. G196-G203 ◽  
Author(s):  
John Wong ◽  
Paul Kubes ◽  
Yikun Zhang ◽  
Yang Li ◽  
Stefan J. Urbanski ◽  
...  
Keyword(s):  
Allograft Rejection ◽  
Leukocyte Adhesion ◽  
Leukocyte Recruitment ◽  
Intercellular Adhesion Molecule ◽  
Brown Norway ◽  
Intercellular Adhesion Molecule 1 ◽  
Cell Recruitment ◽  
Hepatic Allograft

The pathogenesis of hepatic allograft rejection remains unclear. We aimed to clarify the early role of intercellular adhesion molecule-1 (ICAM-1)-mediated cell recruitment in chronic hepatic rejection. Liver transplantation was performed from Lewis to Lewis rats (isograft controls) and from Lewis to Brown Norway rats (allograft rejection group). The allografted rats were treated with either ICAM-1 antisense oligonucleotides (10 mg · kg−1· day−1× 6 days ip) or a control preparation (either ICAM-1 missense oligonucleotide or normal saline). Hepatic leukocyte recruitment in vivo was studied on day 6 by using intravital microscopy. Liver histology, biochemistry, and survival rates were also examined. Leukocyte adhesion in terminal hepatic venules was significantly increased in the rejection group compared with isograft controls. Antisense ICAM-1 in the allografted group effectively reduced leukocyte adhesion. Histology and liver chemistry were less deranged in the antisense-treated groups compared with control-treated allografted rats. In the allograft groups, survival was significantly prolonged in the antisense-treated rats (42.3 ± 1.2 days) compared with the controls (25.2 ± 2.7 days). These results showed that early leukocyte recruitment in the hepatic microvasculature of rejecting allografts is ICAM-1 dependent and suggest that impacting on early cell recruitment can significantly ameliorate chronic rejection.

Role of Mac-1 and ICAM-1 in ischemia-reperfusion injury in a microcirculation model of BALB/C mice

1994 ◽  
Vol 267 (4) ◽  
pp. H1320-H1328 ◽  
Author(s):  
D. Nolte ◽  
R. Hecht ◽  
P. Schmid ◽  
A. Botzlar ◽  
M. D. Menger ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Fluorescein Isothiocyanate ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Capillary Perfusion ◽  
Inflammatory Reactions

The leukocyte beta 2-integrin Mac-1 (CD11b/CD18) and its endothelial ligand intercellular adhesion molecule 1 (ICAM-1) are involved in leukocyte adhesion to and macromolecular leakage from postcapillary venules during inflammatory reactions. Both events are also encountered after ischemia-reperfusion of striated muscle, suggesting a central role of both adhesion proteins in reperfusion injury. Using intravital fluorescence microscopy and a microcirculation model in awake BALB/C mice, we investigated the effects of monoclonal antibodies (MAb) and Fab fragments to Mac-1 and MAb to ICAM-1 on leukocyte-endothelium interaction and macromolecular leakage of fluorescein isothiocyanate-dextran (1.5 x 10(5) mol wt) in striated skin muscle after 3 h of ischemia followed by reperfusion. We demonstrated that administration of MAb and Fab to Mac-1 before reperfusion was as effective as administration of MAb to ICAM-1, which was found to be significantly upregulated in the postischemic tissue by immunohistochemical analysis, in preventing postischemic leukocyte adhesion to and macromolecular leakage from postcapillary venules, whereas postischemic leukocyte rolling was not affected after MAb administration. Postischemic capillary perfusion was efficiently preserved in animals treated with anti-Mac-1 and anti-ICAM-1 MAb compared with animals receiving the isotype-matched control antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Role of Hyphal Formation in Interactions ofCandida albicans with Endothelial Cells

2000 ◽  
Vol 68 (6) ◽  
pp. 3485-3490 ◽  
Author(s):  
Quynh T. Phan ◽  
Paul H. Belanger ◽  
Scott G. Filler
Keyword(s):  
Endothelial Cells ◽  
Leukocyte Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Proinflammatory Response ◽  
Regulatory Pathways ◽  
Ofcandida Albicans ◽  
Hyphal Formation

ABSTRACT The ability to change from yeast to hyphal morphology is a major virulence determinant of Candida albicans. Mutants with defined defects in filamentation regulatory pathways have reduced virulence in mice. However, is it poorly understood why hyphal formation is critical for C. albicans to cause hematogenously disseminated infections. We used recently constructed mutants to examine the role of hyphal formation in the interactions ofC. albicans with endothelial cells in vitro. These interactions included the ability of the mutants to invade and injure endothelial cells. Because the formation of hyphae may influence the host inflammatory response to C. albicans, we also investigated the capacity of these mutants to stimulate endothelial cells to express E-selectin and intercellular adhesion molecule 1. We infected endothelial cells with C. albicans strains containing homozygous null mutations in the following filamentation regulatory genes: CLA4, CPH1,EFG1, and TUP1. Whereas the wild-type strain formed true hyphae on endothelial cells, we found that neither the Δefg1 nor the Δcph1 Δefg1double mutant germinated. The Δtup1 mutant formed only pseudohyphae. We also found that the Δefg1, Δcph1 Δefg1, and Δtup1 mutants had significantly reduced capacities to invade and injure endothelial cells. Therefore, Efg1p and Tup1p contribute to virulence by regulating hyphal formation and the factors that enable C. albicans to invade and injure endothelial cells. With the exception of the Δcph1 Δefg1 mutant, all other mutants stimulated endothelial cells to express at least one of the leukocyte adhesion molecules. Therefore, the combined activities of Cph1p and Efg1p are required for C. albicans to stimulate a proinflammatory response in endothelial cells.

scholarly journals Endothelial-dependent Mechanisms Regulate Leukocyte Transmigration: A Process Involving the Proteasome and Disruption of the Vascular Endothelial–Cadherin Complex at Endothelial Cell-to-Cell Junctions

1997 ◽  
Vol 186 (4) ◽  
pp. 517-527 ◽  
Author(s):  
Jennifer R. Allport ◽  
Han Ding ◽  
Tucker Collins ◽  
Mary E. Gerritsen ◽  
Francis W. Luscinskas
Keyword(s):  
Endothelial Cell ◽  
Adhesion Molecule ◽  
Umbilical Vein ◽  
Cell Junctions ◽  
Intercellular Adhesion Molecule ◽  
Neutrophil Adhesion ◽  
Vascular Endothelial ◽  
Intercellular Adhesion Molecule 1 ◽  
Leukocyte Transmigration

Although several adhesion molecules expressed on leukocytes (β1 and β2 integrins, platelet endothelial cell adhesion molecule 1 [PECAM-1], and CD47) and on endothelium (intercellular adhesion molecule 1, PECAM-1) have been implicated in leukocyte transendothelial migration, less is known about the role of endothelial lateral junctions during this process. We have shown previously (Read, M.A., A.S. Neish, F.W. Luscinskas, V.J. Palambella, T. Maniatis, and T. Collins. 1995. Immunity. 2:493–506) that inhibitors of the proteasome reduce lymphocyte and neutrophil adhesion and transmigration across TNF-α–activated human umbilical vein endothelial cell (EC) monolayers in an in vitro flow model. The current study examined EC lateral junction proteins, principally the vascular endothelial (VE)–cadherin complex and the effects of proteasome inhibitors (MG132 and lactacystin) on lateral junctions during leukocyte adhesion, to gain a better understanding of the role of EC junctions in leukocyte transmigration. Both biochemical and indirect immunofluorescence analyses of the adherens junction zone of EC monolayers revealed that neutrophil adhesion, not transmigration, induced disruption of the VE–cadherin complex and loss of its lateral junction localization. In contrast, PECAM-1, which is located at lateral junctions and is implicated in neutrophil transmigration, was not altered. These findings identify new and interrelated endothelial-dependent mechanisms for leukocyte transmigration that involve alterations in lateral junction structure and a proteasome-dependent event(s).

Mechanisms underlying the anti-inflammatory actions of central corticotropin-releasing factor

1999 ◽  
Vol 276 (4) ◽  
pp. G1016-G1026 ◽  
Author(s):  
Maria Casadevall ◽  
Esteban Saperas ◽  
Julián Panés ◽  
Azucena Salas ◽  
Donald C. Anderson ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Inflammatory Responses ◽  
Leukocyte Adhesion ◽  
Corticotropin Releasing Factor ◽  
Cell Interactions ◽  
Leukocyte Recruitment ◽  
Intercellular Adhesion Molecule ◽  
High Dose ◽  
Intercellular Adhesion Molecule 1 ◽  
Anti Inflammatory

Immune activation of hypothalamic corticotropin-releasing factor (CRF) provides a negative feedback mechanism to modulate peripheral inflammatory responses. We investigated whether central CRF attenuates endothelial expression of intercellular adhesion molecule 1 (ICAM-1) and leukocyte recruitment during endotoxemia in rats and determined its mechanisms of action. As measured by intravital microscopy, lipopolysaccharide (LPS) induced a dose-dependent increase in leukocyte rolling, adhesion, and emigration in mesenteric venules, which was associated with upregulation of endothelial ICAM-1 expression. Intracisternal injection of CRF abrogated both the increased expression of ICAM-1 and leukocyte recruitment. Intravenous injection of the specific CRF receptor antagonist astressin did not modify leukocyte-endothelial cell interactions induced by a high dose of LPS but enhanced leukocyte adhesion induced by a low dose. Blockade of endogenous glucocorticoids but not α-melanocyte-stimulating hormone (α-MSH) receptors reversed the inhibitory action of CRF on leukocyte-endothelial cell interactions during endotoxemia. In conclusion, cerebral CRF blunts endothelial upregulation of ICAM-1 and attenuates the recruitment of leukocytes during endotoxemia. The anti-inflammatory effects of CRF are mediated by adrenocortical activation and additional mechanisms independent of α-MSH.

Adhesion molecules contribute to ischemia and reperfusion-induced injury in the isolated rat lung

1995 ◽  
Vol 78 (6) ◽  
pp. 2245-2252 ◽  
Author(s):  
T. M. Moore ◽  
P. Khimenko ◽  
W. K. Adkins ◽  
M. Miyasaka ◽  
A. E. Taylor
Keyword(s):  
Endothelial Cell ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Leukocyte Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Ischemia And Reperfusion ◽  
Intercellular Adhesion Molecule 1 ◽  
Endothelial Cell Adhesion Molecules ◽  
Permeability Increase ◽  
Isolated Rat Lung

Leukocyte adherence to the endothelium after ischemia and reperfusion contributes to microvascular injury in most organs. The purpose of this study was to evaluate the leukocyte and endothelial cell adhesion molecules involved with ischemia-reperfusion (I/R)-induced pulmonary microvascular injury in the isolated rat lung. After 45 min of ischemia and 30 min of reperfusion, microvascular permeability was significantly increased and lung retention of leukocytes occurred. Pretreatment with monoclonal antibodies against the leukocyte adhesion molecule CD18 or the endothelial cell adhesion molecules intercellular adhesion molecule 1 and P-selectin significantly attenuated the I/R-induced permeability increase and lung sequestration of neutrophils, mononuclear leukocytes, and eosinophils. In contrast, immunoneutralization of the rat leukocyte adhesion molecule L-selectin neither protected against the I/R-induced permeability increase nor prevented lung sequestration of neutrophils and eosinophils. We conclude that leukocyte adherence in the pulmonary, microvasculature and subsequent permeability increase after I/R is dependent on the integrin CD18, its endothelial cell ligand intercellular adhesion molecule 1, and the endothelial cell rolling factor P-selectin but not the leukocyte rolling factor L-selectin.

Selectin-independent leukocyte rolling and adhesion in mice deficient in E-, P-, and L-selectin and ICAM-1

2001 ◽  
Vol 280 (2) ◽  
pp. H634-H641 ◽  
Author(s):  
S. Bradley Forlow ◽  
Klaus Ley
Keyword(s):  
Adhesion Molecules ◽  
Leukocyte Adhesion ◽  
Leukocyte Recruitment ◽  
Intercellular Adhesion Molecule ◽  
Striking Similarity ◽  
Leukocyte Rolling ◽  
Intercellular Adhesion Molecule 1 ◽  
Cell Recruitment ◽  
Adhesion Efficiency

To study selectin-independent leukocyte recruitment and the role of intercellular adhesion molecule-1 (ICAM-1), we generated mice lacking all three selectins and ICAM-1 (E/P/L/I−/−) by bone marrow transplantation. These mice were viable and appeared healthy under vivarium conditions, although they showed a 97% reduction in leukocyte rolling, a 63% reduction in leukocyte firm adhesion, and a 99% reduction of neutrophil recruitment in a thioglycollate-induced model of peritonitis at 4 and 24 h. Mononuclear cell recruitment was almost unaffected. All residual leukocyte rolling and most leukocyte adhesion in these mice depended on α4-integrins, but a small number of leukocytes (6% of wild-type control) still became adherent in the absence of all known rolling mechanisms (E-, P-, L-selectin and α4-integrins). A striking similarity of leukocyte adhesion efficiency in E/P/L−/− and E/P/I−/− mice suggests a pathway in which leukocyte rolling through L-selectin requires ICAM-1 for adhesion and recruitment. Comparison of our data with mice lacking individual or other combinations of adhesion molecules reveal that elimination of more adhesion molecules further reduces leukocyte recruitment but the effect is less than additive.

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