Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA295986 | ENA |
REPOSITORIES: ENA
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Project description:Brain inflammation, a common feature in neurodegenerative diseases, is a complex series of events, which can be detrimental and even lead to neuronal death. Nonetheless, several studies suggest that inflammatory signals are also positively influencing neural cell proliferation, survival, migration and differentiation. Recently, correlative studies suggested that astrocytes are able to dedifferentiate upon injury, and may thereby re-acquire neural stem cells (NSC) potential. However, the mechanism underlying this dedifferentiation process upon injury remains unclear. In this study, we find that during the early response of reactive gliosis, inflammation induces a conversion of mature astrocytes into neural progenitors. A TNF treatment induces the decrease of specific astrocyte markers, such as GFAP or genes related to glycogen metabolism, while a subset of these cells re-express immaturity markers, such as CD44, Musashi-1 and Oct4. Thus, TNF treatment results in the appearance of cells that exhibit a neural progenitor phenotype and are able to proliferate and differentiate into neurons and/or astrocytes. This dedifferentiation process is maintained as long as TNF is present in the culture medium. In addition, we identify a role for Oct4 in this process, since the TNF-induced dedifferentiation can be prevented by inhibiting Oct4 expression. Our results show that activation of the NF-kB pathway through TNF plays an important role in the dedifferentiation of astrocytes via the re-expression of Oct4. These findings indicate that the first step of reactive gliosis is in fact a dedifferentiation process of resident astrocytes mediated by the NF-kB pathway. This dedifferentiation process is maintained as long as TNF is present in the culture medium. In addition, we identify a role for Oct4 in this process, since the TNF-induced dedifferentiation can be prevented by inhibiting Oct4 expression. Our results show that activation of the NF-kB pathway through TNF plays an important role in the dedifferentiation of astrocytes via the re-expression of Oct4. These findings indicate that the first step of reactive gliosis is in fact a dedifferentiation process of resident astrocytes mediated by the NF-kB pathway.
2015-09-16 | GSE73022 | GEO
Project description:We demonstrate that persistent NF-KB activation affects neural progenitor cells-derived astrocytes differentiation
2021-04-11 | GSE117736 | GEO
Project description:Brain inflammation, a common feature in neurodegenerative diseases, is a complex series of events, which can be detrimental and even lead to neuronal death. Nonetheless, several studies suggest that inflammatory signals are also positively influencing neural cell proliferation, survival, migration and differentiation. Recently, correlative studies suggested that astrocytes are able to dedifferentiate upon injury, and may thereby re-acquire neural stem cells (NSC) potential. However, the mechanism underlying this dedifferentiation process upon injury remains unclear. In this study, we find that during the early response of reactive gliosis, inflammation induces a conversion of mature astrocytes into neural progenitors. A TNF treatment induces the decrease of specific astrocyte markers, such as GFAP or genes related to glycogen metabolism, while a subset of these cells re-express immaturity markers, such as CD44, Musashi-1 and Oct4. Thus, TNF treatment results in the appearance of cells that exhibit a neural progenitor phenotype and are able to proliferate and differentiate into neurons and/or astrocytes. This dedifferentiation process is maintained as long as TNF is present in the culture medium. In addition, we identify a role for Oct4 in this process, since the TNF-induced dedifferentiation can be prevented by inhibiting Oct4 expression. Our results show that activation of the NF-kB pathway through TNF plays an important role in the dedifferentiation of astrocytes via the re-expression of Oct4. These findings indicate that the first step of reactive gliosis is in fact a dedifferentiation process of resident astrocytes mediated by the NF-kB pathway. This dedifferentiation process is maintained as long as TNF is present in the culture medium. In addition, we identify a role for Oct4 in this process, since the TNF-induced dedifferentiation can be prevented by inhibiting Oct4 expression. Our results show that activation of the NF-kB pathway through TNF plays an important role in the dedifferentiation of astrocytes via the re-expression of Oct4. These findings indicate that the first step of reactive gliosis is in fact a dedifferentiation process of resident astrocytes mediated by the NF-kB pathway. Cultures of primary mouse astrocytes were treated with TNF (50 ng/mL) for 24 hours. Cells were collected and immediately homogenized in cooled down RNA NOW reagent (OZYME). Total RNA was extracted according to RNA NOW manufacturer's recommendations with -20°C overnight incubation for small RNA precipitation. Total RNA integrity and purity were assessed using the Agilent 2100 Bioanalyzer and RNA 6000 Nano LabChip kits (Agilent Technologies). Only good-quality RNA (no contamination or degradation, RIN > 9) was used and further processed. Total RNA samples were reverse-transcribed to double-stranded cDNA using specific primers, which reduce the priming of rRNA. cRNA was generated by in vitro transcription and reverse transcribed into a sense single-stranded cDNA. The cDNA was fragmented, labeled, and hybridized onto Affymetrix GeneChip Mouse Gene 1.0 ST Arrays according to the Ambion Whole Transcript Expression kit for Affymetrix GeneChip Whole Transcript Expression Array Protocol (P/N 4425209 Rev.B 05/2009) and GeneChip WT Terminal Labeling and Hybridization User Manual for use with the Ambion Whole Transcript Expression kit (P/N 702808 Rev.6). Microarrays were then washed, stained, and scanned according to the manufacturer's instructions. The samples cover combinations of 7 time points (0H, 6H, 24H, 48H, 72H, 1W, 2W) and two conditions (TNF and control), with multiple replicates per condition and time point.
2015-09-16 | E-GEOD-73022 | biostudies-arrayexpress
Project description:Astrocytes contribute to the pathogenesis of multiple sclerosis (MS); however, the mechanisms underlying the regulation of astrocytic responses remain unknown. Here we report an exhaustive molecular and functional characterization of astrocyte reactivity following exposure to cerebrospinal fluid (CSF) from MS patients classified according to the degree of inflammatory activity. We showed that mouse astrocytes exposed to CSF from patients with high inflammatory activity (MS-High) exhibited a specific pro-inflammatory reactive state that was characterized by enhanced NF-kB signalling. This reactive astrocyte state conferred a dysfunctional response through an altered pro-inflammatory secretome that drove neuronal dysfunction and impaired synaptic plasticity. SerpinE1 was identified as a potential downstream mediator of the non-cell-autonomous toxic effect on neuronal function based on its significant up-regulation in secretomes from astrocytes exposed to CSF from MS-high patients. Further, we identified chitinase 3-like 1 as a potential upstream modulator of astrocyte reactivity via activation of NF-kB signalling based on its significantly increased levels in the CSF from MS-High patients. Taken together our findings indicate that the inflammatory microenvironment in the central nervous system of MS patients can induce specific reactive astrocyte states that trigger neuronal degeneration and may ultimately contribute to disease progression.
2022-06-23 | PXD027152 | Pride
Project description:Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcome. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. NF-kB activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion derived equally from infiltrating monocytes and resident tissue. Moreover, NF-kB activated cells and macrophages undergo crosstalk: whereas NF-kB+ cells recruit macrophages to inhibit regeneration and promote atrophy, while interestingly also protecting myofibers, macrophages stimulate NF-kB+ cells in a feed forward loop to sustain inflammation. Together, we propose that NF-kB functions in multiple cells in the muscle microenvironment to stimulate macrophage inflammation that both promotes and protects against muscle wasting in cancer.
2025-01-15 | GSE248800 | GEO
Project description:Astrocytes are taking the center stage in neurotrauma and neurological disease as they appear to play a dominant role in the inflammatory processes associated with these conditions. Previously, we reported that inhibiting nuclear factor kappa B (NF-kB) activation in astrocytes, by using a transgenic mouse model (GFAP-IκBα-dn mice), results in improved functional recovery following spinal cord injury (SCI), with increased white matter preservation and axonal sparing. In the present study we sought to determine whether this improvement, due to inhibiting NF-k-B activation in astrocytes, could be the result of enhanced oligogenesis in our GFAP-IκBα-dn mice. To gain insight into the underlying molecular mechanisms, we performed microarray analysis in naïve and 3 days, 3 and 6 weeks following SCI in GFAP-IκBα-dn and wild type (WT) littermate mice. Surprisingly, we found the largest number of genes differentially regulated between GFAP-IκBα-dn and WT mice 6 weeks post-injury. Interestingly, the data suggested that inhibiting astroglial NF-kB alters the inflammatory environment to support oligogenesis. Furthermore, confirmation of microarray data with qPCR and western blotting analysis and using BrdU labeling along with cell specific immunohistochemistry, confocal microscopy and quantitative cell counts, we demonstrate a significant increase in oligogenesis in GFAP-IκBα-dn following SCI. These studies suggest that therapeutic strategies targeting NF-kB activation in the CNS following SCI may promote oligogenesis and remyelination. Wild type (WT) mice - time points naïve, 3 days, 3 weeks, 6 weeks. Transgenic mice (TG) - time points naïve, 3 days, 3 weeks, 6 weeks.
2013-09-01 | E-GEOD-46695 | biostudies-arrayexpress
Project description:Nf-kB activity is associated with the key pathological features of chronic respiratory diseases including epithelial remodelling, excess mucous production, and submucosal gland hyperplasia. However, the role of Nf-kB activity in airway epithelial differentiation remains controversial. In the present study we demonstrate that Nf-kB adaptor protein Myd88 deficiency promotes increased airway submucosal gland abundance and abnormal epithelial differentiation in proximal adult airways. Abnormal airway differentiation was not developmentally determined, became exacerbated following acute lung injury, and did not involve altered epithelial proliferation or apoptosis. Instead, we demonstrate that tracheal Myd88 deficiency promotes upregulation of a unique gene expression profile that includes activation of alternate, Myd88-independent Nf-kB signalling. Finally, we show that these effects are not intrinsically maintained in vitro using an air-liquid interface epithelial culture. This finding indicates that Myd88 deficiency promotes adult airway remodelling by regulating non-epithelial, non-cell autonomous Nf-kB activity. 20 microarray samples of whole trachea RNA in total: 5 samples wildtype control tissue 5 samples Myd88 KO control tissue 5 samples wildtype 3 day polidocanol injury tissue 5 samples Myd88 KO 3 day polidocanol injury tissue
2011-03-17 | E-GEOD-17268 | biostudies-arrayexpress
Project description:Chronic NF-kB activation in inflammation and cancer has long been linked to persistent activation of NF-kB–responsive gene promoters. However, NF-kB factors also massively bind to gene bodies. Here, we demonstrate that recruitment of the NF-kB factor RELA to intragenic regions regulates alternative splicing upon NF-kB activation by the viral oncogene Tax of HTLV-1. Integrative analyses of RNA splicing and chromatin occupancy, combined with chromatin tethering assays, demonstrate that DNA-bound RELA interacts with and recruits the splicing regulator DDX17, in an NF-kB activation–dependent manner. This leads to alternative splicing of target exons due to the RNA helicase activity of DDX17. Similar results were obtained upon Tax-independent NF-kB activation, indicating that Tax likely exacerbates a physiological process where RELA provides splice target specificity. Collectively, our results demonstrate a physical and direct involvement of NF-kB in alternative splicing regulation, which significantly revisits our knowledge of HTLV-1 pathogenesis and other NF-kB–related diseases.
2020-05-12 | GSE123752 | GEO
Project description:Astrogliosis is an inflammatory process by which astrocytes undergo morphological, transcriptional, and functional changes that primarily contribute to tissue healing and restore CNS homeostasis as a response to neuroinflammation. However, excessive astrocyte activation causes neuronal death, immune cell activation and infiltration, and chronic neuroinflammation. The advent of human induced pluripotent stem cell (hiPSC)-derived three-dimensional (3D) models has aided research of complex CNS processes by generating complex structures of neural cells able to decode the molecular mechanisms that trigger and sustain astrocyte activation and drive microenvironment remodeling in the human CNS. Despite depicting interactions between different brain cell types and their microenvironment, the lack of reproducibility, and immature/activated cell phenotypes typical of these models limit their utility to address neuroinflammation mechanisms. Here we establish a hiPSC-derived model of neuroinflammation to dissect cellular crosstalk along the neuroinflammatory axis. A methodology pioneered by our team was used, in which hiPSC-derived neural progenitors were cultured in perfusion stirred-tank bioreactors and differentiated into 3D neurospheroids composed of neurons, astrocytes, and oligodendrocytes. This model recapitulates specific features of the brain microenvironment, such as human brain-like ECM deposition and neuron-glia functional interactions. The neurospheroids were challenged with prototypical inflammatory factors reported to induce activation of astrocytes in mice models, namely TNF-α, IL-α, and C1q. By performing whole transcriptome analysis (RNAseq), we observed an upregulation of several inflammatory-related genes associated with TNF and NF-kB signaling (e.g., CXCL5, CCL2, TNAIP3, and NFKB2). Whole proteome analysis (SWATH-MS) also depicted the enrichment of proteins involved in cell response to stress and cytokine regulation, namely TXLNA, DCTN5, and NOLC1. Concomitantly, time course analysis of conditioned media from the stimulated neurospheroids exhibited increased secretion of inflammation-related cytokines (e.g., CCL2, CXCL10, IL-6, and IL-8). Astrocytes in challenged neurospheroids displayed an impaired capacity for clearance of extracellular glutamate and secretion of glutamine compared to the unstimulated control, indicating functional impairment and known molecular effects of TNF signaling. Together, these results further demonstrate astrocyte functionality within the neurospheroids, which undergo canonical astrogliosis events that are considered hallmarks of neuroinflammation. The human neurospheroid model described may contribute to better understand the mechanisms governing human astrogliosis and be used as a platform to study glial-neuron mature interactions during acute stimulation and inflammation.
2025-07-28 | PXD043835 | Pride
Project description:Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with two major biological subtypes, activated B-cell like (ABC) and germinal center B-cell-like (GCB) DLCBL. Self-antigen engagement of B-cell receptors (BCRs) in ABC tumors promotes their clustering in the plasma membrane, thereby initiating chronic active signaling and downstream activation of the pro-survival NF-kB and PI3 kinase pathways. The potential of therapeutics targeting chronic active BCR signaling in ABC DLBCL is highlighted by the frequent response of these tumors to inhibitors of BTK, a kinase that links BCR signaling to NF-kB activation. Here we used genome-wide CRISPR-Cas9 screens to identify regulators of the IRF4, a direct NF-kB target and essential transcription factor in ABC cells. Unexpectedly, inactivation of the oligosaccharyltransferase (OST) complex, which mediates N-linked protein glycosylation, reduced IRF4 expression and NF-kB activity in ABC cells, resulting in cell death. Using functional glycoproteogenomics we linked this phenomenon to defective BCR glycosylation. Pharmacologic inhibition of OST reduced the size and abundance of BCR microclusters in the plasma membrane and blocked their internalization. These reorganized BCRs associated with the inhibitory coreceptor CD22, which attenuated proximal BCR signaling, thereby reducing NF-kB and PI3 kinase activation. OST inhibition also blocked the trafficking of TLR9 to the endolysosomal compartment, preventing its association with the BCR in the My-T-BCR signaling complex that activates NF-kB in ABC cells. In GCB DLBCL, OST inhibition also attenuated constitutive BCR signaling, reducing PI3 kinase signaling and triggering cell death. Our data highlight the therapeutic potential of OST inhibitors for the treatment of diverse B cell malignancies in which constitutive BCR signaling is essential.
2023-04-24 | PXD038951 | Pride