IL-1β promotes transendothelial migration of PBMCs by upregulation of the FN/α5β1 signalling pathway in immortalised human brain microvascular endothelial cells

Labus, Josephine; Wöltje, Kerstin; Stolte, Kim Natalie; Häckel, Sonja; Kim, Kwang Sik; Hildmann, Annette; Danker, Kerstin

doi:10.1016/j.yexcr.2018.10.002

Cited by 37 publications

(31 citation statements)

References 51 publications

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“…The present study showed the importance of intact FN in the maintenance of normal endothelial integrity by demonstrating that pUR4 led to endothelial leakage in the unstimulated situation. However, the interaction between cells and the ECM was altered under the pathological condition, and CNS insults can strongly reinduce β1 integrin expression in endothelial cells [12]; furthermore, β1 integrin–mediated signaling can promote vascular leakage during inflammation [13, 56]. Our and other laboratories have reported that CNS insults significantly upregulate FN expression in addition to that of β1 integrin in the endothelial cells of microvessels [12]; thus, increased FN–β1 integrin interaction may drive endothelial barrier disruption.…”

Section: Discussionmentioning

confidence: 99%

“…β1 integrin is the predominant integrin expressed in the endothelial lining of CNS vessels [4, 11, 12]. Several β1-containing integrins are detected in the endothelial cells of the CNS vasculatures, including α1β1, α2β1, α3β1, α5β1, α6β1, and αvβ1 [13–15]. In healthy situations, β1 integrin–ECM engagement induces integrin signaling cascades that modulate the expression of the tight junction proteins and maintain the endothelial cell integrity of the CNS microvessels [4, 16].…”

Section: Introductionmentioning

confidence: 99%

“…In healthy situations, β1 integrin–ECM engagement induces integrin signaling cascades that modulate the expression of the tight junction proteins and maintain the endothelial cell integrity of the CNS microvessels [4, 16]. However, under the pathological condition, ECM composition changes and β1 integrin–ECM interaction increases; thus, endothelial integrity is disrupted [13, 17].…”

Section: Introductionmentioning

confidence: 99%

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Fibronectin inhibitor pUR4 attenuates tumor necrosis factor α–induced endothelial hyperpermeability by modulating β1 integrin activation

2019

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Background The blood–spinal cord barrier (BSCB) is composed of a monolayer of endothelium linked with tight junctions and extracellular matrix (ECM)-rich basement membranes and is surrounded by astrocyte foot processes. Endothelial permeability is regulated by interaction between endothelial cells and ECM proteins. Fibronectin (FN) is a principal ECM component of microvessels. Excessive FN deposition disrupts cell–cell adhesion in fibroblasts through β1 integrin ligation. To determine whether excessive FN deposition contributes to the disruption of endothelial integrity, we used an in vitro model of the endothelial monolayer to investigate whether the FN inhibitor pUR4 prevents FN deposition into the subendothelial matrix and attenuates endothelial leakage. Methods To correlate the effects of excessive FN accumulation in microvessels on BSCB disruption, spinal nerve ligation—which induces BSCB leakage—was applied, and FN expression in the spinal cord was evaluated through immunohistochemistry and immunoblotting. To elucidate the effects by which pUR4 modulates endothelial permeability, brain-derived endothelial (bEND.3) cells treated with tumor necrosis factor (TNF)-α were used to mimic a leaky BSCB. A bEND.3 monolayer was preincubated with pUR4 before TNF-α treatment. The transendothelial electrical resistance (TEER) measurement and transendothelial permeability assay were applied to assess the endothelial integrity of the bEND.3 monolayer. Immunofluorescence analysis and immunoblotting were performed to evaluate the inhibitory effects of pUR4 on TNF-α-induced FN deposition. To determine the mechanisms underlying pUR4-mediated endothelial permeability, cell morphology, stress fiber formation, myosin light chain (MLC) phosphorylation, and β1 integrin–mediated signaling were evaluated through immunofluorescence analysis and immunoblotting. Results Excessive FN was accumulated in the microvessels of the spinal cord after spinal nerve ligation; moreover, pUR4 inhibited TNF-α-induced FN deposition in the bEND.3 monolayer and maintained intact TEER and endothelial permeability. Furthermore, pUR4 reduced cell morphology alteration, actin stress fiber formation, and MLC phosphorylation, thereby attenuating paracellular gap formation. Moreover, pUR4 reduced β1 integrin activation and downstream signaling. Conclusions pUR4 reduces TNF-α-induced β1 integrin activation by depleting ECM FN, leading to a decrease in endothelial hyperpermeability and maintenance of monolayer integrity. These findings suggest therapeutic benefits of pUR4 in pathological vascular leakage treatment. Electronic supplementary material The online version of this article (10.1186/s12929-019-0529-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fibronectin inhibitor pUR4 attenuates tumor necrosis factor α–induced endothelial hyperpermeability by modulating β1 integrin activation

2019

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“…Additionally, α 5 β 1 is necessary for leukocyte adhesion. Only inhibition of both α 5 β 1 and β 2 integrins completely blocks adhesion in vitro (Pierini et al, 2000), while inhibition of α 5 β 1 alone prevents transmigration across the BBB (Labus et al, 2018) in vitro . As an RGD receptor, fibronectin has been shown to be the primary and preferred [over other potential ligands such as fibrinogen (Suehiro et al, 1997)] ligand for α 5 β 1 on endothelial cells and leukocytes (Schaffner et al, 2013; Bharadwaj et al, 2017).…”

Section: Role Of Integrins Post-stroke: An Overviewmentioning

confidence: 99%

The Inflammatory Response After Ischemic Stroke: Targeting β2 and β1 Integrins

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2019

Front. Neurosci.

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Ischemic stroke is a leading cause of death and disability with limited therapeutic options. Resulting inflammatory mechanisms after reperfusion (removal of the thrombus) result in cytokine activation, calcium influx, and leukocytic infiltration to the area of ischemia. In particular, leukocytes migrate toward areas of inflammation by use of integrins, particularly integrins β 1 and β 2 . Integrins have been shown to be necessary for leukocyte adhesion and migration, and thus are of immediate interest in many inflammatory diseases, including ischemic stroke. In this review, we identify the main integrins involved in leukocytic migration following stroke (α L β 2 , α D β 2 , α 4 β 1 , and α 5 β 1 ) and targeted clinical therapeutic interventions.

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“…Interestingly, another member of the synuclein family, γ‐synuclein better known for its role in tumorgenesis and stimulation of cell migration and invasion, also uses integrin signal pathway by interacting with integrin β1 (ITGB1 or CD29) and integrin–focal adhesion kinase (FAK) signaling pathway (Liu, Qu, Zhao, & Shou, ). Integrin β1 subunit is a member of the subgroup of the β1 integrins consisting of 12 different members (Labus et al, ) . Ligands of β1 integrins are primarily components of the extracellular matrix.…”

mentioning

confidence: 99%