T cell-specific deletion of TRAIL-receptor reveals a critical role for pathologic T cell activation and inflammation in experimental autoimmune encephalomyelitis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE179758 | GEO | 2021/07/11
REPOSITORIES: GEO
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Project description:Experimental autoimmune encephalomyelitis (EAE) is a murine model of multiple sclerosis, a chronic neurodegenerative and inflammatory autoimmune condition of the central nervous system (CNS). Pathology is driven by the infiltration of autoreactive CD4+ lymphocytes into the CNS where they attack neuronal sheaths causing ascending paralysis. We used an isotope-coded protein labelling approach to investigate the proteome of CD4+ cells isolated from the spinal cord and brain of mice at various stages of EAE progression in two EAE disease models; PLP139-151-induced relapsing-remitting EAE and MOG35-55-induced chronic EAE, which emulate the two forms of human multiple sclerosis. A total of 1120 proteins were quantified across disease onset, peak-disease and remission phases of disease and of these, 13 up-regulated proteins of interest were identified with functions relating to the regulation of inflammation, leukocyte adhesion and migration, tissue repair and the regulation of transcription/translation. Proteins implicated in processes such as inflammation (S100A4 and S100A9) and tissue repair (Annexin A1), which represent key events during EAE progression were validated by quantitative PCR. This is the first targeted analysis of autoreactive cells purified from the CNS during EAE, highlighting fundamental CD4+ cell-driven processes that occur during the initiation of relapse and remission stages of disease.
2016-07-08 | PXD001011 | Pride
Project description:Histone deacetylases are key epigenetic regulators that control T cell-mediated immunity. A T cell-specific deletion of Hdac1 (HDAC1cKO) protects mice against experimental autoimmune encephalomyelitis (EAE). However, it remains elusive whether inhibition of HDAC1 enzymatic activity and thus mimicking HDAC1 inhibitor treatment is sufficient to block EAE induction. In order to address this question, we generated a novel mouse strain that expresses catalytically inactive HDAC1 (HDAC1Off) from the Rosa26 locus in HDAC1cKO CD4+ T cells to mimic selective inhibition of HDAC1 enzymatic activity in vivo. Mice expressing wildtype HDAC1 in HDAC1cKO CD4+ T cells (HDAC1On) were generated as corresponding controls. In contrast to HDAC1On mice, HDAC1Off mice did not develop EAE, and this correlated with diminished leukocyte CNS infiltration. HDAC1Off CD4+ T cells in the CNS displayed a severe reduction of IFNγ, IL-17A and TNFα proinflammatory cytokine expression. In vivo activated HDAC1Off CD4+ T cells downregulated gene sets associated with T cell activation, inflammatory response and cell migration, indicating impaired effector functions of HDAC1Off CD4+ T cells. Thus, our study demonstrates that the inhibition of the catalytic activity of HDAC1 is sufficient to achieve a clinical benefit in EAE disease development. This raises the exciting translational perspective that targeting HDAC1 enzymatic activity is a promising therapeutic strategy in treating human T cell-mediated autoimmune diseases.
2024-10-25 | GSE228259 | GEO
Project description:Purpose: To elucidate the potential immune-regulatory mechanism of TRAIL of activated T cells in EAE, we analyzed gene expression profiles of splenic CD4+ T cells from EAE mice treated with TRAIL by RNA sequencing and transcriptome analysis. Methods: Splenic CD4+ T cell mRNA profiles of control or EAE mice treated with vehicle or TRAIL were generated by deep sequencing using Illumina Solexa. Library construction of all samples were used by Agilent's SureSelect Strand Specific RNA Library Preparation Kit for 75SE (Single-End or Paired-End) sequencing on Solexa platform. The sequence was directly determined using sequencing-by-synthesis technology via the TruSeq SBS Kit. Raw sequences were obtained from the Illumina Pipeline software bcl2fastq v2.0 and expected to generate 20M (million reads or Gb) per sample. Results: By comparing mRNA exression of splenic CD4+ T cells from EAE mice treated with vehicle or TRAIL, there were 244 genes significantly differentially expressed. By analyzing these 244 significant genes categorized by a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, the most significantly enriched category for CD4+ T cells was “cell cycle” (multiple of enrichment: 3.13, p = 1.64 × 10−5) followed by “TCR signaling pathway” (multiple of enrichment: 2.80, p = 8.25 × 10−4). In addition, significant genes in the“TCR signaling pathway” tended to be downregulated while those in “cell cycle”tended to be upregulated in a volcano plot analysis. Consistent with the volcano plot results, by using unsupervised hierarchical clustering, the heatmap showed that significant TCR signaling pathway-associated genes were downregulated, while significant cell cycle-associated genes were upregulated in splenic CD4+ T cells from EAE mice treated with TRAIL Conclusions: Our study demonstrated the gene transcription pattern from CD4+ T cells of TRAIL-treated EAE mice were involved in distinct TCR signaling and cell cycle pathways.
2017-12-27 | GSE108523 | GEO
Project description:Transcriptional profiling of subventricular zone (SVZ) progenitors comparing control healthy mice to mice induced to develop an autoimmune demyelination (EAE model). Goal was to unveil genes involved in demyelination-induced reactivity of SVZ progenitors. Two-condition experiment, healthy vs. EAE derived SVZ progenitors. Biological replicates: 2 control replicates, 2 EAE replicates. SVZ progenitors were sorted in two cell populations: neuronal progenitors (PSA-NCAM magnetic sorting) and glial progenitors (NG2 magnetic sorting). Progenitors from healthy mice are reference samples.
2013-09-09 | E-GEOD-47486 | biostudies-arrayexpress
Project description:In this study we determined whole genome gene expression of murine naive CD4+ T cells, in vitro differentiated Th17 cells, and CD4+ T cells isolated from experimental autoimmune encephalitomyelitis (EAE)-affected animals either after adoptive transfer of Th17 cells or after immunization with MOG35-55-peptide. The overall goal was to identify candidate genes involved in T cell pathology, encephalitogenicity and plasticity. These findings could then be correlated to multiple sclerosis pathology. Naive CD4+ T cells were isolated from B6.2d2 transgenic mice with MOG-specific T cell receptors and differentiated in vitro into Th17 cells. These Th17 cells were adoptively transferred into lymphopenic RAG1-/- mice to induce EAE. Further, EAE was induced by immunizing wild-type C57BL/6 mice with MOG35-55 peptide. RNA was extracted from naive CD4+ T cells, Th17 cells, and from CD4+ T cells isolated from the CNS of EAE-affected mice for gene expression analysis. Replicates from three independent experiments were analyzed.
2015-02-26 | E-GEOD-57098 | biostudies-arrayexpress
Project description:Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS); its cause is unknown. To understand the pathogenesis of MS, researchers often use the experimental autoimmune encephalomyelitis (EAE) mouse model. Here, our aim was to build a proteome map of the biological changes that occur during MS at the major onset sites—the brain and the spinal cord. We performed quantitative proteome profiling in five specific brain regions and the spinal cord of EAE and healthy mice with high-resolution mass spectrometry based on tandem mass tags.
2019-02-25 | PXD011428 | Pride
Project description:Innate receptors, including Toll like receptors (TLRs), are implicated in pathogenesis of CNS inflammatory diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). TLR response to pathogens or endogenous signals includes production of immunoregulatory mediators. One of these, interferon (IFN)β, a Type I IFN, plays a protective role in MS and EAE. We have previously shown that intrathecal administration of selected TLR ligands induced IFNβ and infiltration of blood-derived myeloid cells into the CNS, and suppressed EAE in mice. We have now extended these studies to evaluate a potential therapeutic role for CNS-endogenous TLR7 and TLR9. Intrathecal application of Imiquimod (TLR7 ligand) or CpG oligonucleotide (TLR9 ligand) into CNS of otherwise unmanipulated mice induced IFNβ expression, with greater magnitude in response to CpG. CNS extraparenchymal CD45+ cells were identified as source of IFNβ. Intrathecal CpG induced infiltration of monocytes, neutrophils, CD4+ T cells and NK cells whereas Imiquimod did not recruit blood-derived CD45+ cells. CpG, but not Imiquimod, had a beneficial effect on EAE, when given at time of disease onset. This therapeutic effect of CpG on EAE was not seen in mice lacking the Type I IFN receptor. In mice with EAE treated with CpG, the proportion of monocytes was significantly increased in the CNS. Infiltrating cells were predominantly localized to spinal cord meninges and demyelination was significantly reduced compared to non-treated mice with EAE. Our findings show that TLR7 and TLR9 signaling induce distinct inflammatory responses in the CNS with different outcome in EAE and point to recruitment of blood-derived cells and IFNβ induction as possible mechanistic links between TLR9 stimulation and amelioration of EAE. The protective role of TLR9 signaling in the CNS may have application in treatment of diseases such as MS.
2021-04-15 | GSE172083 | GEO
Project description:Compelling evidence has shown that interferon (IFN)-γ has dual effects in multiple sclerosis and in its animal model of experimental autoimmune encephalomyelitis (EAE), with results supporting both a pathogenic and beneficial function. However, the mechanisms whereby IFN-γ may promote neuroprotection in EAE and its effects on central nervous system (CNS)-resident cells have remained an enigma for more than 30 years. In this study, the impact of IFN-γ at the peak of EAE, its effects on CNS infiltrating myeloid cells (MC) and microglia (MG), and the underlying cellular and molecular mechanisms were investigated. IFN-γ administration resulted in disease amelioration and attenuation of neuroinflammation associated with significantly lower frequencies of CNS CD11b+ myeloid cells and less infiltration of inflammatory cells and demyelination. A significant reduction in activated MG and enhanced resting MG was determined by flow cytometry and immunohistrochemistry. Primary MC/MG cultures obtained from spinal cord of IFN-γ-treated EAE mice that were ex vivo re-stimulated with a low dose (1 ng/ml) of IFN-γ and neuroantigen promoted a significantly higher induction of CD4+ regulatory T (Treg) cells associated with increased transforming growth factor (TGF)-β secretion. Additionally, IFN-γ-treated primary MC/MG cultures produced significantly lower nitrite in response to LPS challenge than control MC/MG. IFN-γ-treated EAE mice had a significantly higher frequency of CX3CR1high MC/MG and expressed lower levels of program death ligand 1 (PD-L1) than PBS-treated mice. Most CX3CR1highPD-L1lowCD11b+Ly6G- cells expressed MG markers (Tmem119, Sall2, and P2ry12), indicating that they represented an enriched MG subset (CX3CR1highPD-L1low MG). Amelioration of clinical symptoms and induction of CX3CR1highPD-L1low MG by IFN-γ were dependent on STAT-1. RNA-seq analyses revealed that in vivo treatment with IFN-γ promoted the induction of homeostatic CX3CR1highPD-L1low MG, upregulating the expression of genes associated with tolerogenic and anti-inflammatory roles and down-regulating pro-inflammatory genes. These analyses highlight the master role that IFN-γ plays in regulating microglial activity and provide new insights into the cellular and molecular mechanisms involved in the therapeutic activity of IFN-γ in EAE.
2023-05-11 | GSE231833 | GEO
Project description:Transcriptional profiling of subventricular zone (SVZ) progenitors comparing control healthy mice to mice induced to develop an autoimmune demyelination (EAE model). Goal was to unveil genes involved in demyelination-induced reactivity of SVZ progenitors.
2013-09-09 | GSE47486 | GEO
Project description:Background/Aims:Increasing evidence have associated mitochondrial dysfunction and reactive oxygen species (ROS) generation to neuron loss in multiple sclerosis (MS). PGC-1α regulates mitochondrial biogenesis and respiration and plays a pivotal role in modulating ROS levels. Here, we investigated the potential function of peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) in the mammalian MS disease model, EAE experimental autoimmune encephalomyelitis (EAE). Methods:We used WT mice to evaluate the change of PGC during the course of EAE. The transgenic mice with neuron-specific overexpression of PGC-1α was applied to explore how PGC1 in neuron affects EAE outcome. A neuronal cell line of lentivirus transfection leading to PGC-1α markedly increased was applied to verify the protective effects of PGC1 in neurons. RNA-seq was employed to explore the potential target genes and signaling pathways. Results: We observed that PGC-1α were decreased at 13d, continuously decreased at 20d, then mildly increased at 30d in wild-type (WT) EAE mice, which is accompanied with alterations of mitochondrial antioxidants SOD2, Prx3, Trx2 and UCP4,5. Our study revealed that PGC-1αf/f Eno2-Cre mice improved EAE clinical symptoms, ameliorated inflammation and demyelination in spinal cords, increased mitochondrial antioxidants SOD2, Prx3, Trx2 and UCPs, reduced the production of ROS and inhibited the apoptotic pathways. In addition, PGC-1αf/f Eno2-Cre mice showed decreased apoptotic neurons compared with the WT EAE mice. In vitro, overexpressing PGC-1α by lentivirus transfection revealed similar results with that of in vivo by using NSC-34 cells treated with 1mg/ml lipopolysaccharide (LPS). Furthermore, RNA-seq analysis showed that apoptotic processes were significantly enriched in the top 10 significant GO terms of differentially expressed (DE) gene and apotosis pathway was significantly enriched in KEGG pathway analysis. Conclusion: Taken together, our findings indicate that upregulation of neuronal PGC-1α protected neuron apotosis in EAE and in vitro.
2021-04-30 | GSE130177 | GEO