MicroRNA regulation in experimental autoimmune encephalomyelitis in mice and marmosets resembles regulation in human multiple sclerosis lesions

Lescher, Juliane; Paap, Franziska; Schultz, Verena; Redenbach, Laura; Scheidt, Uta; Rosewich, Hendrik; Nessler, Stefan; Fuchs, Eberhard; Gärtner, Jutta; Brück, Wolfgang; Junker, Andreas

doi:10.1016/j.jneuroim.2012.02.012

Cited by 48 publications

(51 citation statements)

References 62 publications

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“…Recently, the expression of several miRNAs has been identified and demonstrated to be up-regulated in mononuclear cells of peripheral blood or active lesions derived from patients with relapsing-remitting MS and EAE mice (13)(14)(15)(16). However, the expression profiles and functions of miRNAs both in the brain tissue of EAE mice and in the astrocytes stimulated with IL-17 are still unknown.…”

Section: Interleukin 17 (Il-17) Produced Mainly By T Helper 17 (Th17mentioning

confidence: 99%

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Interleukin-17 (IL-17)-induced MicroRNA 873 (miR-873) Contributes to the Pathogenesis of Experimental Autoimmune Encephalomyelitis by Targeting A20 Ubiquitin-editing Enzyme

Liu

Pang

et al. 2014

Journal of Biological Chemistry

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Background:The regulatory mechanism of abnormal miRNA expression in astrocytes upon IL-17 stimulation remains unclear. Results: miR-873 induced by IL-17 promotes inflammatory cytokine production and aggravates demyelination in experimental autoimmune encephalomyelitis (EAE) through the A20/NF-B pathway. Conclusion: IL-17 regulates miRNA expression in astrocytes, which affects the pathogenesis of EAE. Significance: These data provide a novel regulatory mechanism in inflammatory autoimmunity diseases.

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Section: Interleukin 17 (Il-17) Produced Mainly By T Helper 17 (Th17mentioning

confidence: 99%

“…Error bars, S.E. (15,16,26,27). However, the changes of miRNA expression profiles both in the brain tissue of EAE mice (in vivo) and in the astrocytes upon IL-17 stimulation (in vitro) remain unclear.…”

Section: Production Of Il-6 Tnf-␣ Mip-2 and Mcp-1/5 And The Expresmentioning

confidence: 99%

Interleukin-17 (IL-17)-induced MicroRNA 873 (miR-873) Contributes to the Pathogenesis of Experimental Autoimmune Encephalomyelitis by Targeting A20 Ubiquitin-editing Enzyme

Liu

Pang

et al. 2014

Journal of Biological Chemistry

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“…Data Kramer et al, 2015) likely involved in MS/EAE pathogenesis and potentially useful as a diagnostic marker for MS (Keller et al, 2009;Gandhi, 2015). Interestingly, miR-142-3p is highly expressed in blood and WM lesions of patients with MS and of EAE mice (Junker et al, 2009;Keller et al, 2009;Waschbisch et al, 2011;Angerstein et al, 2012;Lescher et al, 2012;.…”

Section: Discussionmentioning

confidence: 99%

“…Small noncoding microRNAs (miRNAs) regulate several physiological and pathological processes by repressing post-transcriptionally target messenger RNAs (mRNAs) (Bartel, 2009), and are good candidates in the inflammatory synaptic damage (Ceman and Saugstad, 2011). Significant changes of miRNA expression profiles have been detected in blood cells of patients with MS and in lesions of the white matter (WM) both in MS and in EAE (Junker et al, 2011;Angerstein et al, 2012;Lescher et al, 2012;Thamilarasan et al, 2012;Ode et al, 2013;Gandhi, 2015). Recently, profiling of miRNAs has been explored also in the CSF of MS patients (Haghikia et al, 2012;Bergman et al, 2016), as potential diagnostic marker.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, profiling of miRNAs has been explored also in the CSF of MS patients (Haghikia et al, 2012;Bergman et al, 2016), as potential diagnostic marker. Dysregulated miRNAs have been associated with astrocyte activation and infiltrating immune cells in WM lesions (Junker et al, 2011;Ode et al, 2013;, and it has also been observed that demyelination affects neuronal miRNAs in MS hippocampus (Dutta et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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MicroRNAs (miRNA) play an important role in post-transcriptional gene regulation of several physiological and pathological processes. In multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the CNS, and in its mouse model, the experimental autoimmune encephalomyelitis (EAE), miRNA dysregulation has been mainly related to immune system dysfunction and white matter (WM) pathology. However, little is known about their role in gray matter pathology. Here, we explored miRNA involvement in the inflammation-driven alterations of synaptic structure and function, collectively known as synaptopathy, a neuropathological process contributing to excitotoxic neurodegeneration in MS/EAE. Particularly, we observed that miR-142-3p is increased in the CSF of patients with active MS and in EAE brains. We propose miR-142-3p as a molecular mediator of the IL-1␤-dependent downregulation of the glial glutamate-aspartate transporter (GLAST), which causes an enhancement of the glutamatergic transmission in the EAE cerebellum. The synaptic abnormalities mediated by IL-1␤ and the clinical and neuropathological manifestations of EAE disappeared in miR-142 knockout mice. Furthermore, we observed that in vivo miR-142-3p inhibition, either by a preventive and local treatment or by a therapeutic and systemic strategy, abolished IL-1␤-and GLAST-dependent synaptopathy in EAE wild-type mice. Consistently, miR-142-3p was responsible for the glutamatergic synaptic alterations caused by CSF of patients with MS, and CSF levels of miR-142-3p correlated with prospective MS disease progression. Our findings highlight miR-142-3p as key molecular player in IL-1␤-mediated synaptic dysfunction, possibly leading to excitotoxic damage in both EAE and MS diseases. Inhibition of miR-142-3p could be neuroprotective in MS.

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Traumatic brain injury increases levels of miR‐21 in extracellular vesicles: implications for neuroinflammation

et al. 2016

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Traumatic brain injury (TBI) is an important health concern and effective treatment strategies remain elusive. Understanding the complex multicellular response to TBI may provide new avenues for intervention. In the context of TBI, cell–cell communication is critical. One relatively unexplored form of cell–cell communication in TBI is extracellular vesicles (EVs). These membrane‐bound vesicles can carry many different types of cargo between cells. Recently, miRNA in EVs have been shown to mediate neuroinflammation and neuronal injury. To explore the role of EV‐associated miRNA in TBI, we isolated EVs from the brain of injured mice and controls, purified RNA from brain EVs, and performed miRNA sequencing. We found that the expression of miR‐212 decreased, while miR‐21, miR‐146, miR‐7a, and miR‐7b were significantly increased with injury, with miR‐21 showing the largest change between conditions. The expression of miR‐21 in the brain was primarily localized to neurons near the lesion site. Interestingly, adjacent to these miR‐21‐expressing neurons were activated microglia. The concurrent increase in miR‐21 in EVs with the elevation of miR‐21 in neurons, suggests that miR‐21 is secreted from neurons as potential EV cargo. Thus, this study reveals a new potential mechanism of cell–cell communication not previously described in TBI.

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MicroRNA regulation in experimental autoimmune encephalomyelitis in mice and marmosets resembles regulation in human multiple sclerosis lesions

Cited by 48 publications

References 62 publications

Interleukin-17 (IL-17)-induced MicroRNA 873 (miR-873) Contributes to the Pathogenesis of Experimental Autoimmune Encephalomyelitis by Targeting A20 Ubiquitin-editing Enzyme

Interleukin-17 (IL-17)-induced MicroRNA 873 (miR-873) Contributes to the Pathogenesis of Experimental Autoimmune Encephalomyelitis by Targeting A20 Ubiquitin-editing Enzyme

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

Traumatic brain injury increases levels of miR‐21 in extracellular vesicles: implications for neuroinflammation

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