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NFATc1 deficiency in T cells protects mice from experimental autoimmune encephalomyelitis.

ABSTRACT: NFATc1 is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors. NFAT is activated upon T-cell receptor activation followed by intracytoplasmatic calcium influx where calmodulin, a calcium sensor protein, activates the phosphatase calcineurin that dephosphorylates NFAT proteins and results in NFAT nuclear import. Here, we show the analysis of conditional NFATc1-deficient mice bearing a deletion of NFATc1 in CD4(+) and CD8(+) T cells. NFATc1-deficient CD4(+) T cells polarized under Th17 conditions express reduced levels of the Th17-associated transcription factor RORγT (where ROR is RAR-related orphan receptor) as well as the Th17-associated cytokines IL-17A, IL-17F, IL-21, and IL-10. In the murine model of experimental EAE, we found a strong reduction of the disease outcome in conditional NFATc1-deficient mice, as compared with control littermates. This was accompanied by a diminished inflammation in the brain and spinal cord and reduced IL-17A and IFN-γ expression by antigen-specific spleen, spinal cord, and brain cells. Altogether, these results reveal an important role of NFATc1 in inducing Th17-cell responses and IFN-γ, both being relevant for the EAE development.

SUBMITTER: Reppert S

PROVIDER: S-EPMC6681150 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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NFATc1 deficiency in T cells protects mice from experimental autoimmune encephalomyelitis.

Reppert Sarah S Zinser Elisabeth E Holzinger Corinna C Sandrock Lena L Koch Sonja S Finotto Susetta S

European journal of immunology 20150330 5

NFATc1 is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors. NFAT is activated upon T-cell receptor activation followed by intracytoplasmatic calcium influx where calmodulin, a calcium sensor protein, activates the phosphatase calcineurin that dephosphorylates NFAT proteins and results in NFAT nuclear import. Here, we show the analysis of conditional NFATc1-deficient mice bearing a deletion of NFATc1 in CD4(+) and CD8(+) T cells. NFATc1-deficient CD4(+) T ...[more]

PMID: 25689841

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Project description:Phytocannabinoids that do not produce psychotropic effects are considered of special interest as novel therapeutic agents in CNS diseases. A cannabigerol quinone, the compound VCE-003, has been shown to alleviate symptoms in a viral model of multiple sclerosis (MS). Hence, we studied T cells and macrophages as targets for VCE-003 and its efficacy in an autoimmune model of MS. Proliferation, cell cycle, expression of activation markers was assessed by FACs in human primary T cells, and cytokine and chemokine production was evaluated. Transcription was studied in Jurkat cells and RAW264.7 cells were used to study the effects of VCE-003 on IL-17-induced macrophage polarization to a M1 phenotype. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG₃₅₋₅₅) immunization and spinal cord pathology was assessed by immunohistochemistry. Neurological impairment was evaluated using disease scores. We show here that VCE-003 inhibits CD3/CD28-induced proliferation, cell cycle progression and the expression of the IL-2Rα and ICAM-1 activation markers in human primary T cells. VCE-003 inhibits the secretion of Th1/Th17 cytokines and chemokines in primary murine T cells, and it reduces the transcriptional activity of the IL-2, IL-17 and TNFα promoters induced by CD3/CD28. In addition, VCE-003 and JWH-133, a selective CB2 agonist, dampened the IL-17-induced polarization of macrophages to a pro-inflammatory M1 profile. VCE-003 also prevented LPS-induced iNOS expression in microglia. VCE-003 ameliorates the neurological defects and the severity of MOG-induced EAE in mice through CB2 and PPARγ receptor activation. A reduction in cell infiltrates, mainly CD4+ T cells, was observed, and Th1 and Th17 responses were inhibited in the spinal cord of VCE-003-treated mice, accompanied by weaker microglial activation, structural preservation of myelin sheets and reduced axonal damage. This study highlights the therapeutic potential of VCE-003 as an agent for the treatment of human immune diseases with both inflammatory and autoimmune components.

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.

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NFATc1 deficiency in T cells protects mice from experimental autoimmune encephalomyelitis.

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NFATc1 deficiency in T cells protects mice from experimental autoimmune encephalomyelitis.

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