Lipid Rafts Direct Macrophage Motility in the Tissue Microenvironment

Previtera, Michelle L.; Peterman, Kimberly; Shah, Smit; Luzuriaga, Juan

doi:10.1007/s10439-014-1142-1

Cited by 10 publications

(6 citation statements)

References 33 publications

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“…To determine the effect of substrate stiffness on the TLR4 signaling pathway, we first evaluated TLR4 expression in US and LPS–stimulated BMMs grown on collagen–PDL–functionalized 0.3 and 230 kPa gels. These two extreme stiffnesses were chosen because BMMs grown on these PA gels showed the most signficant differences in proinflammatory mediator concentrations and cell morphology remained homogenous on both 0.3 and 230 kPa gels [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

Substrate Stiffness Regulates Proinflammatory Mediator Production through TLR4 Activity in Macrophages

2015

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Clinical data show that disease adversely affects tissue elasticity or stiffness. While macrophage activity plays a critical role in driving disease pathology, there are limited data available on the effects of tissue stiffness on macrophage activity. In this study, the effects of substrate stiffness on inflammatory mediator production by macrophages were investigated. Bone marrow–derived macrophages were grown on polyacrylamide gels that mimicked the stiffness of a variety of soft biological tissues. Overall, macrophages grown on soft substrates produced less proinflammatory mediators than macrophages grown on stiff substrates when the endotoxin LPS was added to media. In addition, the pathways involved in stiffness–regulated proinflammation were investigated. The TLR4 signaling pathway was examined by evaluating TLR4, p–NF–κB p65, MyD88, and p–IκBα expression as well as p–NF–κB p65 translocation. Expression and translocation of the various signaling molecules were higher in macrophages grown on stiff substrates than on soft substrates. Furthermore, TLR4 knockout experiments showed that TLR4 activity enhanced proinflammation on stiff substrates. In conclusion, these results suggest that proinflammatory mediator production initiated by TLR4 is mechanically regulated in macrophages.

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Section: Resultsmentioning

confidence: 99%

Substrate Stiffness Regulates Proinflammatory Mediator Production through TLR4 Activity in Macrophages

2015

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“…5,6,55,56) Furthermore, Michelle et al reported that macrophage single cell migration stimulated by lipopolysaccharide depends on ECM stiffness and disruption of the lipid rafts impairs stiffness dependency. 61) Taken together, these observations indicate that lipid rafts are required for ECM stiffness regulation of cell migration.…”

Section: Discussionmentioning

confidence: 74%

The distribution of vinculin to lipid rafts plays an important role in sensing stiffness of extracellular matrix

Nagasato

Yamashita

Matsuo

et al. 2017

Bioscience, Biotechnology, and Biochemistry

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Extracellular matrix (ECM) stiffness regulates cell differentiation, survival, and migration. Our previous study has shown that the interaction of the focal adhesion protein vinculin with vinexin α plays a critical role in sensing ECM stiffness and regulating stiffness-dependent cell migration. However, the mechanism how vinculin-vinexin α interaction affects stiffness-dependent cell migration is unclear. Lipid rafts are membrane microdomains that are known to affect ECM-induced signals and cell behaviors. Here, we show that vinculin and vinexin α can localize to lipid rafts. Cell-ECM adhesion, intracellular tension, and a rigid ECM promote vinculin distribution to lipid rafts. The disruption of lipid rafts with Methyl-β-cyclodextrin impaired the ECM stiffness-mediated regulation of vinculin behavior and rapid cell migration on rigid ECM. These results indicate that lipid rafts play an important role in ECM-stiffness regulation of cell migration via vinculin.

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“…Lipid rafts are discrete cell-membrane structures enriched with cholesterol and glycosphingolipids where various signaling receptors, including syndecans [28] and integrins [29], accumulate and cross talk. Lipid rafts are typically found at the leading edge of migrating macrophages and have been implicated in cell adhesion, cytoskeleton organization, spreading, migration and extravasation [29,30]. We then wondered whether lipid rafts were necessary for SYN-NCs to spread onto Tat.…”

Section: Lymphocyte Adhesion and Spreading Onto Substrate-immobilized Tatmentioning

confidence: 99%

HIV-1 Tat and Heparan Sulfate Proteoglycans Orchestrate the Setup of in Cis and in Trans Cell-Surface Interactions Functional to Lymphocyte Trans-Endothelial Migration

et al. 2021

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HIV-1 transactivating factor Tat is released by infected cells. Extracellular Tat homodimerizes and engages several receptors, including integrins, vascular endothelial growth factor receptor 2 (VEGFR2) and heparan sulfate proteoglycan (HSPG) syndecan-1 expressed on various cells. By means of experimental cell models recapitulating the processes of lymphocyte trans-endothelial migration, here, we demonstrate that upon association with syndecan-1 expressed on lymphocytes, Tat triggers simultaneously the in cis activation of lymphocytes themselves and the in trans activation of endothelial cells (ECs). This “two-way” activation eventually induces lymphocyte adhesion and spreading onto the substrate and vascular endothelial (VE)-cadherin reorganization at the EC junctions, with consequent endothelial permeabilization, leading to an increased extravasation of Tat-presenting lymphocytes. By means of a panel of biochemical activation assays and specific synthetic inhibitors, we demonstrate that during the above-mentioned processes, syndecan-1, integrins, FAK, src and ERK1/2 engagement and activation are needed in the lymphocytes, while VEGFR2, integrin, src and ERK1/2 are needed in the endothelium. In conclusion, the Tat/syndecan-1 complex plays a central role in orchestrating the setup of the various in cis and in trans multimeric complexes at the EC/lymphocyte interface. Thus, by means of computational molecular modelling, docking and dynamics, we also provide a characterization at an atomic level of the binding modes of the Tat/heparin interaction, with heparin herein used as a structural analogue of the heparan sulfate chains of syndecan-1.

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Lipid Rafts Direct Macrophage Motility in the Tissue Microenvironment

Cited by 10 publications

References 33 publications

Substrate Stiffness Regulates Proinflammatory Mediator Production through TLR4 Activity in Macrophages

Substrate Stiffness Regulates Proinflammatory Mediator Production through TLR4 Activity in Macrophages

The distribution of vinculin to lipid rafts plays an important role in sensing stiffness of extracellular matrix

HIV-1 Tat and Heparan Sulfate Proteoglycans Orchestrate the Setup of in Cis and in Trans Cell-Surface Interactions Functional to Lymphocyte Trans-Endothelial Migration

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