RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration

Buul, Jaap D. van; Allingham, Michael J.; Samson, Thomas D.; Meller, Julia; Boulter, Etienne; Garcı́a-Mata, Rafael; Burridge, Keith

doi:10.1083/jcb.200612053

Cited by 195 publications

(221 citation statements)

References 31 publications

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“…transmigratory cups, apical cups, dome structures, ICAM-1-enriched contact areas, or actin dynamic structures. 14,[67][68][69][70][71] The names were based on the hypothesized function or morphology of these structures. Work of Carman and coworkers showed that these structures, that formed both during para-and transcellular diapedesis (Fig.…”

Section: Paracellular and Transcellular Migrationmentioning

confidence: 99%

“…75,76 It has been shown that assembly of F-actin, the major component and driving force to induce such apical protrusions, requires the activation small GTPases RhoG and Rac1. 67,77 Currently, the major function of the docking structure is thought to provide guidance for transmigrating leukocytes. 78 The regulation of the endothelial F-actin cytoskeleton Regulation of leukocyte TEM and vascular integrity both depend on the ability to dynamically remodel the F-actin cytoskeleton in ECs.…”

Section: Paracellular and Transcellular Migrationmentioning

confidence: 99%

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Leukocyte transendothelial migration: A local affair

2016

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Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens. It serves as a protective response that involves leukocytes, blood vessels and molecular mediators with the purpose to eliminate the initial cause of cell injury and to initiate tissue repair. Inflammation is tightly regulated by the body and is associated with transient crossing of leukocytes through the blood vessel wall, a process called transendothelial migration (TEM) or diapedesis. TEM is a close collaboration between leukocytes on one hand and the endothelium on the other. Limiting vascular leakage during TEM but also when the leukocyte has crossed the endothelium is essential for maintaining vascular homeostasis. Although many details have been uncovered during the recent years, the molecular mechanisms from the vascular part that drive TEM still shows significant gaps in our understanding. This review will focus on the local signals that are induced in the endothelium that regulate leukocyte TEM and simultaneous preservation of endothelial barrier function.

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Section: Paracellular and Transcellular Migrationmentioning

confidence: 99%

Section: Paracellular and Transcellular Migrationmentioning

confidence: 99%

Leukocyte transendothelial migration: A local affair

2016

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“…It has been established that cross linking of ICAM-1 or VCAM-1 results in activation of Rac1 (17,32). Moreover, ICAM-1 or VCAM-1 clustering is essential in the formation of docking structures, required for proper leukocyte transendothelial migration, for which Rac1 is the molecular engine (14,16).…”

Section: -Mp/6-t-gtp Inhibit Icam-1 Mediated Docking Structure Formamentioning

confidence: 99%

“…ICAM-1 mAb (R&D Systems) to create ICAM-1-Ab-coated beads to induce docking structure formation on endothelial cells (17).…”

Section: Western Blot Analysismentioning

confidence: 99%

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Inhibition of GTPase Rac1 in Endothelium by 6-Mercaptopurine Results in Immunosuppression in Nonimmune Cells: New Target for an Old Drug

Marinković

Kroon

Hoogenboezem

et al. 2014

The Journal of Immunology

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Azathioprine and its metabolite 6-mercaptopurine (6-MP) are well established immunosuppressive drugs. Common understanding of their immunosuppressive properties is largely limited to immune cells. However, in this study, the mechanism underlying the protective role of 6-MP in endothelial cell activation is investigated. Because 6-MP and its derivative 6-thioguanosine-5′-triphosphate (6-T-GTP) were shown to block activation of GTPase Rac1 in T lymphocytes, we focused on Rac1-mediated processes in endothelial cells. Indeed, 6-MP and 6-T-GTP decreased Rac1 activation in endothelial cells. As a result, the compounds inhibited TNF-α–induced downstream signaling via JNK and reduced activation of transcription factors c-Jun, activating transcription factor-2 and, in addition, NF κ-light-chain-enhancer of activated B cells (NF-κB), which led to decreased transcription of proinflammatory cytokines. Moreover, 6-MP and 6-T-GTP selectively decreased TNF-α–induced VCAM-1 but not ICAM-1 protein levels. Rac1-mediated generation of cell membrane protrusions, which form docking structures to capture leukocytes, also was reduced by 6-MP/6-T-GTP. Consequently, leukocyte transmigration was inhibited after 6-MP/6-T-GTP treatment. These data underscore the anti-inflammatory effect of 6-MP and 6-T-GTP on endothelial cells by blocking Rac1 activation. Our data provide mechanistic insight that supports development of novel Rac1-specific therapeutic approaches against chronic inflammatory diseases.

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Sided Stimulation of Endothelial Cells Modulates Neutrophil Trafficking in an In Vitro Sepsis Model

Ahmad,

Linares,

Pietropaoli

et al. 2024

Adv Healthcare Materials

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Sepsis pathophysiology involves complex interactions between vascular endothelium and circulating immune cells. Importantly, while the role of dysregulated polymorphonuclear leukocyte (PMN) transmigration in septic mediated tissue damage is well documented, strategies to mitigate aberrant transmigration across endothelium have yet to yield viable therapeutics. Much of this can be attributed to the usage of animal models in preclinical trials that lack translational relevance. Recently, however, microphysiological systems (MPS) have emerged as novel in vitro mimetics that facilitate the development of human models of disease. With this advancement, we can now directly probe aspects of endothelial physiology that are difficult to assess with other models. Here, we study the role of endothelial cell (EC) apicobasal polarity and how sided presentation of inflammatory cytokines modulates subsequent leukocyte trafficking response by utilizing the µSiM‐MVM (microphysiological system enabled by a silicon membrane – microvascular mimetic). The apicobasal polarity of ECs with respect to inflammation and leukocyte trafficking is a scarcely studied phenomenon that may be critical to understand the dynamic interplay between ECs and PMNs in sepsis and other causes of systemic inflammation. Here we stimulated ECs either apically or basally with a cytokine cocktail to model a septic‐like challenge before introducing healthy donor PMNs into the device. At low concentrations we found that a tissue sided (basally oriented) stimulation generated a stronger PMN transmigratory response versus apical stimulation. Importantly, healthy PMNs were unable to migrate towards a bacterial peptide chemoattractant when ECs were apically stimulated at low doses. This mimics the impaired ability of PMNs to identify a source of infection seen in sepsis, but identifies an EC role in the impairment for the first time, to our knowledge. Only by escalating the apical inflammatory stimulus by a factor of five were we able to overcome the EC barrier and solicit high PMN transmigration levels from the blood to the tissue side of the chip. These results, using the unique capabilities of the µSiM‐MVM, demonstrate that EC apicobasal polarity modulates differential PMN transmigratory behavior in a way that provides insight into the mechanisms underlying sepsis.This article is protected by copyright. All rights reserved

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RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration

Cited by 195 publications

References 31 publications

Leukocyte transendothelial migration: A local affair

Leukocyte transendothelial migration: A local affair

Inhibition of GTPase Rac1 in Endothelium by 6-Mercaptopurine Results in Immunosuppression in Nonimmune Cells: New Target for an Old Drug

Sided Stimulation of Endothelial Cells Modulates Neutrophil Trafficking in an In Vitro Sepsis Model

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