miR-142-3p Is a Key Regulator of IL-1β-Dependent Synaptopathy in Neuroinflammation

Mandolesi, Georgia; Vito, Francesca De; Musella, Alessandra; Gentile, Antonietta; Bullitta, Silvia; Fresegna, Diego; Sepman, Helena; Sanza, Claudio Di; Haji, Nabila; Mori, Francesco; Buttari, Fabio; Perlas, Emerald; Ciotti, Maria Teresa; Hornstein, Eran; Bozzoni, Irene; Presutti, Carlo; Centonze, Diego

doi:10.1523/jneurosci.0851-16.2017

Cited by 4 publications

(2 citation statements)

References 11 publications

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“…Chronic-progressive EAE was induced as previously described ( 7 ). Briefly, six-eight weeks old C57BL/6 (Charles River, Milan, Italy) female mice were active immunized with an emulsion containing 200 μg/animal of myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55, 85% purity; Espikem, Prato, Italy) in Complete Freund’s Adjuvant (CFA; Difco, Los Altos, CA, USA) containing 8mg/ml lyophilized Mycobacterium tuberculosis (BD, M. Tubercolosis Des.…”

Section: Methodsmentioning

confidence: 99%

Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis

Sanna,

Bruno,

Balletta

et al. 2024

Front. Immunol.

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BackgroundSecondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite treatments advances, a reliable tool able to capture the transition from RRMS to SPMS is lacking. A T cell chimeric MS model demonstrated that T cells derived from relapsing patients exacerbate excitatory transmission of central neurons, a synaptotoxic event absent during remitting stages. We hypothesized the re-emergence of T cell synaptotoxicity during SPMS and investigated the synaptoprotective effects of siponimod, a sphingosine 1-phosphate receptor (S1PR) modulator, known to reduce grey matter damage in SPMS patients.MethodsData from healthy controls (HC), SPMS patients, and siponimod-treated SPMS patients were collected. Chimeric experiments were performed incubating human T cells on murine cortico-striatal slices, and recording spontaneous glutamatergic activity from striatal neurons. Homologous chimeric experiments were executed incubating EAE mice T cells with siponimod and specific S1PR agonists or antagonists to identify the receptor involved in siponimod-mediated synaptic recovery.ResultsSPMS patient-derived T cells significantly increased the striatal excitatory synaptic transmission (n=40 synapses) compared to HC T cells (n=55 synapses), mimicking the glutamatergic alterations observed in active RRMS-T cells. Siponimod treatment rescued SPMS T cells synaptotoxicity (n=51 synapses). Homologous chimeric experiments highlighted S1P5R involvement in the siponimod’s protective effects.ConclusionTransition from RRMS to SPMS involves the reappearance of T cell-mediated synaptotoxicity. Siponimod counteracts T cell-induced excitotoxicity, emphasizing the significance of inflammatory synaptopathy in progressive MS and its potential as a promising pharmacological target.

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Section: Methodsmentioning

confidence: 99%

Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis

Sanna,

Bruno,

Balletta

et al. 2024

Front. Immunol.

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“…For instance, Lei et al (3) demonstrated that miR-142-3p influenced the proliferation of non-small cell lung cancer cells through repression of TGFβR1. miR-142-3p have been highlighted as a key molecular player in IL-1β-mediated synaptic dysfunction, which indicated its neuroprotective role in multiple sclerosis (4). …”

Section: Introductionmentioning

confidence: 99%

microRNA-142-3p inhibits apoptosis and inflammation induced by bleomycin through down-regulation of Cox-2 in MLE-12 cells

Guo

Lin

Ming

et al. 2017

Braz J Med Biol Res

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microRNA (miR)-142-3p is implicated in malignancy and has been identified as a biomarker for aggressive and recurrent lung adenocarcinomas. This study aimed to evaluate the inhibitory effect of miR-142-3p on apoptosis and inflammation induced by bleomycin in MLE-12 cells. MLE-12 cells were first transfected either with miR-142-3p mimic or miR-142-3p inhibitor and then the cells were exposed to 50 μg/mL of bleomycin. Thereafter, cell viability, apoptosis and the expression of pro-inflammatory cytokines were assessed using CCK-8, flow cytometry, RT-PCR and western blot analyses. Cox-2, PI3K, AKT and mTOR expressions were detected by western blotting after bleomycin was administered together with NS-398 (an inhibitor of Cox-2). As a result, cell viability was significantly decreased, as well as apoptosis and the expression of IL-1 and TNF-α were remarkably increased after 50 and 100 μg/mL of bleomycin administration. miR-142-3p overexpression alleviated bleomycin-induced apoptosis and overproduction of these two pro-inflammatory cytokines, while miR-142-3p suppression exhibited completely opposite results. Up-regulation of Cox-2 and inactivation of PI3K/AKT/mTOR were found in bleomycin-pretreated cells, while these abnormal regulations were partially abolished by miR-142-3p overexpression and NS-398. In conclusion, this study demonstrated that miR-142-3p overexpression protected bleomycin-induced injury in lung epithelial MLE-12 cells, possibly via regulating Cox-2 expression and PI3K/AKT/mTOR signaling pathway. These findings provide evidence that miR-142-3p may be a therapeutic strategy for idiopathic pulmonary fibrosis (IPF) treatment.

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MicroRNA-142 regulates inflammation and T cell differentiation in an animal model of multiple sclerosis

Talebi

Ghorbani

Chan

et al. 2017

J Neuroinflammation

106

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BackgroundMicroRNAs have emerged as an important class of modulators of gene expression. These molecules influence protein synthesis through translational repression or degradation of mRNA transcripts. Herein, we investigated the potential role of miR-142a isoforms, miR-142a-3p and miR-142a-5p, in the context of autoimmune neuroinflammation.MethodsThe expression levels of two mature isoforms of miR-142 were measured in the brains of patients with multiple sclerosis (MS) and the CNS tissues from mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Expression analyses were also performed in mitogen and antigen-stimulated splenocytes, as well as macrophages and astrocytes using real-time RT-PCR. The role of the mature miRNAs was then investigated in T cell differentiation by transfection of CD4+ T cells, followed by flow cytometric analysis of intracellular cytokines. Luciferase assays using vectors containing the 3′UTR of predicted targets were performed to confirm the interaction of miRNA sequences with transcripts. Expression of targets were then analyzed in activated splenocytes and MS/EAE tissues.ResultsExpression of miR-142-5p was significantly increased in the frontal white matter from MS patients compared with white matter from non-MS controls. Likewise, expression levels of miR-142a-5p and miR-142a-3p showed significant upregulation in the spinal cords of EAE mice at days 15 and 25 post disease induction. Splenocytes stimulated with myelin oligodendrocyte glycoprotein (MOG) peptide or anti-CD3/anti-CD28 antibodies showed upregulation of miR-142a-5p and miR-142a-3p isoforms, whereas stimulated bone marrow-derived macrophages and primary astrocytes did not show any significant changes in miRNA expression levels. miR-142a-5p overexpression in activated lymphocytes shifted the pattern of T cell differentiation towards Th1 cells. Luciferase assays revealed SOCS1 and TGFBR1 as direct targets of miR-142a-5p and miR-142a-3p, respectively, and overexpression of miRNA mimic sequences suppressed the expression of these target transcripts in lymphocytes. SOCS1 levels were also diminished in MS white matter and EAE spinal cords.ConclusionsOur findings suggest that increased expression of miR-142 isoforms might be involved in the pathogenesis of autoimmune neuroinflammation by influencing T cell differentiation, and this effect could be mediated by interaction of miR-142 isoforms with SOCS1 and TGFBR-1 transcripts.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0832-7) contains supplementary material, which is available to authorized users.

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miR-142-3p Is a Key Regulator of IL-1β-Dependent Synaptopathy in Neuroinflammation

Cited by 4 publications

References 11 publications

Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis

Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis

microRNA-142-3p inhibits apoptosis and inflammation induced by bleomycin through down-regulation of Cox-2 in MLE-12 cells

MicroRNA-142 regulates inflammation and T cell differentiation in an animal model of multiple sclerosis

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