Project description:We used microRNA microarrays to identify dysregulated microRNAs in CD4+ T cells isolated from brains of EAE mice treated with vehicle or THC+CBD.
Project description:STAT5 plays a critical role in mediating cellular responses following cytokine stimulation. The activated STAT5 proteins can form dimers and tetramers with distinct biological functions. The role of STAT5 tetramerization in autoimmune-mediated neuroinflammation has not been investigated. Using the STAT5 tetramer-deficient Stat5a-Stat5b N-domain double knock-in (DKI) mouse strain, we report here that STAT5 tetramers promote the pathogenesis of experimental autoimmune encephalomyelitis (EAE). The mild EAE phenotype observed in DKI mice correlates with the impaired extravasation of pathogenic Th17 cells and interactions between Th17 cells and monocyte-derived cells (MDCs) in the meninges. We further demonstrated that STAT5 tetramerization regulates the GM-CSF-dependent production of CCL17 by MDCs. Importantly, DKI Th17 cells expanded with CCL17 exhibit more severe EAE. Mechanistically, the effect of CCL17 is dependent on the activity of the integrin VLA-4. Thus, our study uncovered a novel GM-CSF-STAT5 tetramer-CCL17 pathway that promotes autoimmune neuroinflammation via the regulation of Th17 cell migration.
Project description:The present study had the purpose to analyze the transcriptional state of oligodendrocytes in an animal model of multiple scleroris resembling autoimmune neuroinflammation and compared with control mice treated with ovalbumin. The results revealed that oligodendrocytes from the EAE (experimental autoimmune encephalomyelitis) model upregulate genes that are involved in immune processes providing evidence that oligodendrocytes can develop an immune phenotype in particular neuroinflammatory conditions.
Project description:Researchers have induced an experimental model of multiple sclerosis [experimental autoimmune encephalomyelitis (EAE)] in mice to investigate the therapeutic effect of the oral treatment with selected Clostridia strains on the clinical outcome of EAE and its mechanisms of action
Project description:Growing evidence are showing a pivotal role of macrophages (MФ) and microglia (MG) in the pathogenesis of Multiple sclerosis (MS). Interferon β (IFN β) and glucocorticoids are front line treatments in MS, and disrupting either type I IFN or GC receptor (GR) pathway in mice aggravates EAE, the mouse model of MS. Here, we evaluated GR Interacting Protein 1 actions in neuroinflammation by subjecting mice conditionally lacking GRIP1 in myeloid cells (cKO) to EAE. We showed that myeloid GRIP1 plays a dual role by promoting the ‘effector’ neuroinflammatory phase of EAE as well as mediating IFN β therapeutic effect. Our sorted MФ/MG transcriptome analysis reveals dramatic changes in inflammatory and IFN-pathway gene expression including potential differences of GRIP1 function in these distinct myeloid cell populations.
Project description:Neuroinflammation causes neuronal injury in multiple sclerosis (MS) and other neurological diseases. MicroRNAs (miRNAs) are central modulators of cellular stress responses, but knowledge about miRNA–mRNA interactions that determine neuronal outcome during inflammation is limited. Here, we combined unbiased neuron-specific miRNA with mRNA sequencing to assemble the regulatory network that mediates robustness against neuroinflammation. As a critical miRNA-network hub we defined miR-92a. Genetic deletion of miR-92a exacerbated the disease course of mice undergoing experimental autoimmune encephalomyelitis (EAE), whereas miR-92a overexpression protected neurons against excitotoxicity. As a key miR-92a target transcript, we identified cytoplasmic polyadenylation element-binding protein 3 (Cpeb3) that was suppressed in inflamed neurons in mouse EAE and human MS. Accordingly, Cpeb3 deletion improved neuronal resistance to excitotoxicity and ameliorated EAE. Together, we discovered that the miR-92a–Cpeb3 axis confers neuronal robustness against inflammation and serves as potential target for neuroprotective therapies.