Human Primary Astrocytes Differently Respond to Pro- and Anti-Inflammatory Stimuli

Szpakowski, Piotr; Książek-Winiarek, Dominika; Turniak-Kusy, Malgorzata; Pacan, Ilona; Głąbiński, Andrzej

doi:10.3390/biomedicines10081769

Cited by 16 publications

(11 citation statements)

References 95 publications

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“…Stressed Ast-AD similarly released increased amounts of sAPPβ, TNF-α, IL-6 and MCP-1, findings not observed in untreated cells. These data corroborate other studies reporting that unstimulated astrocytes did not produce cytokines unless treated with inflammatory mediators, such as those that we used [ 122 ]. In this condition, only miR-21 was found to be enriched in their derived exosomes and may further elicit a pro-inflammatory response [ 123 ].…”

Section: Discussionsupporting

confidence: 92%

Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease

Garcia

Pinto

Ferreira

et al. 2022

Cells

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Alzheimer’s disease (AD) is a neurodegenerative disorder associated with neuron–glia dysfunction and dysregulated miRNAs. We previously reported upregulated miR-124/miR-21 in AD neurons and their exosomes. However, their glial distribution, phenotypic alterations and exosomal spread are scarcely documented. Here, we show glial cell activation and miR-21 overexpression in mouse organotypic hippocampal slices transplanted with SH-SY5Y cells expressing the human APP695 Swedish mutation. The upregulation of miR-21 only in the CSF from a small series of mild cognitive impairment (MCI) AD patients, but not in non-AD MCI individuals, supports its discriminatory potential. Microglia, neurons, and astrocytes differentiated from the same induced pluripotent stem cells from PSEN1ΔE9 AD patients all showed miR-21 elevation. In AD neurons, miR-124/miR-21 overexpression was recapitulated in their exosomes. In AD microglia, the upregulation of iNOS and miR-21/miR-146a supports their activation. AD astrocytes manifested a restrained inflammatory profile, with high miR-21 but low miR-155 and depleted exosomal miRNAs. Their immunostimulation with C1q + IL-1α + TNF-α induced morphological alterations and increased S100B, inflammatory transcripts, sAPPβ, cytokine release and exosomal miR-21. PPARα, a target of miR-21, was found to be repressed in all models, except in neurons, likely due to concomitant miR-125b elevation. The data from these AD models highlight miR-21 as a promising biomarker and a disease-modifying target to be further explored.

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Section: Discussionsupporting

confidence: 92%

Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease

Garcia

Pinto

Ferreira

et al. 2022

Cells

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“…Astrocytes cultured without cytokines were also included. In our previous work, we characterized the secretory activity of astrocytes in response to these stimuli [ 81 ]. After a six-day culture, the media were collected and centrifuged (300× g , 10 min, 20 °C) and the supernatants were centrifuged again (16,000× g , 30 min, 20 °C).…”

Section: Methodsmentioning

confidence: 99%

Astrocyte-Derived Exosomes Differentially Shape T Cells’ Immune Response in MS Patients

Szpakowski

Książek-Winiarek

Czpakowska

et al. 2023

IJMS

Self Cite

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Astrocytes, the most abundant group of glia cells in the brain, provide support for neurons and indicate multiple various functions in the central nervous system (CNS). Growing data additionally describe their role in the regulation of immune system activity. They exert their function not only by direct contact with other cell types, but also through an indirect method, e.g., by secreting various molecules. One such structure is extracellular vesicles, which are important mediators of crosstalk between cells. In our study, we observed that the impact of exosomes derived from astrocytes with various functional phenotype differently affect the immune response of CD4+ T cells, both from healthy individuals and from patients with multiple sclerosis (MS). Astrocytes, by modulating exosome cargo, impacts the release of IFN-γ, IL-17A and CCL2 in our experimental conditions. Considering the proteins concentration in cell culture supernatants and the cellular percentage of Th phenotypes, it could be stated that human astrocytes, by the release of exosomes, are able to modify the activity of human T cells.

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“…Reactive astrocytes expressing CD80 and CD86 have also been identified in patients affected by multiple sclerosis, once more suggesting their potential to work as APCs [ 148 ]. Nevertheless, several controversies exist, since reports have shown that human fetal astrocytes express little CD80 or CD86 mRNA and protein both in unstimulated and cytokine-stimulated conditions [ 149 , 150 ]. Moreover, the in vivo expression of APCs-related molecules needs to be further validated.…”

Section: Transferring Of Protein Aggregates From Neurons To Astrocytesmentioning

confidence: 99%

Brain clearance of protein aggregates: a close-up on astrocytes

Giusti,

Kaur,

Giusto

et al. 2024

Mol Neurodegeneration

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Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation of toxic intra- and extracellular aggregates. Intracellular aggregates can enter the extracellular space and be subsequently transferred among different cell types, thus spreading between connected brain districts.Although microglia perform a predominant role in the removal of extracellular aggregated proteins, mounting evidence suggests that astrocytes actively contribute to the clearing process. However, the molecular mechanisms used by astrocytes to remove misfolded proteins are still largely unknown.Here we first provide a brief overview of the progressive transition from soluble monomers to insoluble fibrils that characterizes amyloid proteins, referring to α-Synuclein and Tau as archetypical examples. We then highlight the mechanisms at the basis of astrocyte-mediated clearance with a focus on their potential ability to recognize, collect, internalize and digest extracellular protein aggregates. Finally, we explore the potential of targeting astrocyte-mediated clearance as a future therapeutic approach for the treatment of neurodegenerative disorders characterized by protein misfolding and accumulation.

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Human Primary Astrocytes Differently Respond to Pro- and Anti-Inflammatory Stimuli

Cited by 16 publications

References 95 publications

Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease

Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease

Astrocyte-Derived Exosomes Differentially Shape T Cells’ Immune Response in MS Patients

Brain clearance of protein aggregates: a close-up on astrocytes

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