ATP increases the migration of microglia across the brain endothelial cell monolayer

Maeda, Tomoji; Inagaki, Manato; Fujita, Yu; Kimoto, Takehiro; Tanabe-Fujimura, Chiaki; Zou, Kun; Liu, Junjun; Komano, Hiroto

doi:10.1042/bsr20160054

Cited by 25 publications

(16 citation statements)

References 27 publications

(29 reference statements)

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“…MMPs, and specifically MMP‐2, play a role in microglia migration and chemotaxis . MMP activation may facilitate microglia migration toward the tumor and may also be important for tumor invasion.…”

Section: Resultsmentioning

confidence: 99%

The metastatic microenvironment: Melanoma–microglia cross‐talk promotes the malignant phenotype of melanoma cells

Izraely

Ben-Menachem

Sagi‐Assif

et al. 2018

Intl Journal of Cancer

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Melanoma has the highest propensity to metastasize to the brain compared to other cancers, as brain metastases are found frequently high in patients who have prolonged survival with visceral metastasis. Once disseminated in the brain, melanoma cells communicate with brain resident cells that include astrocytes and microglia. Microglia cells are the resident macrophages of the brain and are the main immunological cells in the CNS involved in neuroinflammation. Data on the interactions between brain metastatic melanoma cells and microglia and on the role of microglia-mediated neuroinflammation in facilitating melanoma brain metastasis are lacking. To elucidate the role of microglia in melanoma brain metastasis progression, we examined the bidirectional interactions between microglia and melanoma cells in the tumor microenvironment. We identified the molecular and functional modifications occurring in brain-metastasizing melanoma cells and microglia cells after the treatment of each cell type with supernatants of the counter cell type. Both cells induced alteration in gene expression programs, cell signaling, and cytokine secretion in the counter cell type. Moreover, melanoma cells exerted significant morphological changes on microglia cells, enhanced proliferation, induced matrix metalloproteinase-2 (MMP-2) activation, and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype: increased melanoma proliferation, MMP-2 activity, cell migration, brain endothelial penetration, and tumor cells ability to grow as spheroids in 3D cultures. Our work provides a novel insight into the bidirectional interactions between melanoma and micoglia cells, suggesting the contribution of microglia to melanoma brain metastasis formation.

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Section: Resultsmentioning

confidence: 99%

The metastatic microenvironment: Melanoma–microglia cross‐talk promotes the malignant phenotype of melanoma cells

Izraely

Ben-Menachem

Sagi‐Assif

et al. 2018

Intl Journal of Cancer

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“…However, we note that the calcium levels measured in our study could also be sensitive to the culture conditions including the presence of electrospun fibers, ATP dosage and the use of the same substrates for measuring calcium responses before and after ATP addition. Further, although an ATP dose between 1 and 10 µM is known to induce microglia migration within a timeframe of 3–48 hr (Lambert, Ase, Séguéla, & Antel, 2010; Maeda et al, 2016), cell migration was not observed in our study within the short time‐period of 6–7 min that was used for imaging. The focus of the present study was to develop an imaging approach to monitor the effect of ATP treatment through intracellular calcium imaging on electrospun matrices (after 5 min of ATP addition).…”

Section: Discussionmentioning

confidence: 59%

Three‐dimensional imaging and quantification of real‐time cytosolic calcium oscillations in microglial cells cultured on electrospun matrices using laser scanning confocal microscopy

Venkateswarlu

Gare

Dhyani

et al. 2020

Biotech & Bioengineering

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The development of a minimally invasive, robust, and inexpensive technique that permits real‐time monitoring of cell responses on biomaterial scaffolds can improve the eventual outcomes of scaffold‐based tissue engineering strategies. Towards establishing correlations between in situ biological activity and cell fate, we have developed a comprehensive workflow for real‐time volumetric imaging of spatiotemporally varying cytosolic calcium oscillations in pure microglial cells cultured on electrospun meshes. Live HMC3 cells on randomly oriented electrospun fibers were stained with a fluorescent dye and imaged using a laser scanning confocal microscope. Resonance scanning provided high‐resolution in obtaining the time‐course of intracellular calcium levels without compromising spatial and temporal resolution. Three‐dimensional reconstruction and depth‐coding enabled the visualization of cell location and intracellular calcium levels as a function of sample thickness. Importantly, changes in cell morphology and in situ calcium spiking were quantified in response to a soluble biochemical cue and varying matrix architectures (i.e., randomly oriented and aligned fibers). Importantly, raster plots generated from spiking data revealed calcium signatures specific to culture conditions. In the future, our approach can be used to elucidate correlations between calcium signatures and cell phenotype/activation, and facilitate the rational design of scaffolds for biomedical applications.

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“…Several studies have suggested that matrix metalloproteinases (MMPs) play important roles in regulating microglial migration. ATP, speci cally, induces microglial migration by regulating MMP2 and MMP9 [53,80]. Furthermore, MMP2, MMP9, MMP12, and MMP14 have all been found to be increased in LPS-mediated microglial migration [78,81].…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Apolipoprotein E4 expressed by microglia impairs microglial functions and enhances neurotoxicity

Wang

Wei

et al. 2020

Preprint

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Background Microglia, the major cell type that mediates active immune defence in the central nervous system (CNS), constantly survey the brain parenchyma through highly motile processes. Mounting evidence has implicated both beneficial and toxic roles of microglia when over-activated upon neuronal injury. Understanding the function of microglia in the brain may uncover the regulatory mechanisms for neuroinflammation and facilitate the development of a novel therapeutic strategy for Alzheimer's disease (AD). The ε4 allele of apolipoprotein E (APOE) is a major genetic risk factor for the late onset AD. ApoE, as the major cholesterol carrier in the brain, has been implicated in AD pathogenesis. However, how APOE and APOE isoforms directly regulate microglial functions remains largely unknown. Methods Using primary culture of microglia from Apoe knockout (KO) mice, APOE3 and APOE4 targeted replacement (TR) mouse, we investigated the characteristics of microglial secreted apoE particles and the biological effects of apoE isoforms on microglial inflammatory response, migratory ability, cell viability and proliferation. Meanwhile, microglia-neuron co-culture system was utilized to study the effects of apoE isoforms on neurite outgrowth.Results Herein, we found that microglia secret abundant lipidated apoE. Interestingly, apoE4 particles from primary microglia exhibited a higher lipidation status compared to apoE3 particles. Furthermore, apoE4 microglia exhibited a reduced migratory ability as well as enhanced inflammatory responses and neurotoxicity, indicating microglial apoE4 is involved in unfavourable functions. Conclusions Our findings revealed the critical roles for apoE and apoE isoforms in regulating microglial functions. Our results also indicate that targeting apoE-mediated microglial inflammatory responses may serve as a potential therapeutic strategy for AD.

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ATP increases the migration of microglia across the brain endothelial cell monolayer

Cited by 25 publications

References 27 publications

The metastatic microenvironment: Melanoma–microglia cross‐talk promotes the malignant phenotype of melanoma cells

The metastatic microenvironment: Melanoma–microglia cross‐talk promotes the malignant phenotype of melanoma cells

Three‐dimensional imaging and quantification of real‐time cytosolic calcium oscillations in microglial cells cultured on electrospun matrices using laser scanning confocal microscopy

WITHDRAWN: Apolipoprotein E4 expressed by microglia impairs microglial functions and enhances neurotoxicity

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