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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

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Research Article

MiR-142-3p is a Critical Modulator of TNF-mediated Neuronal Toxicity in Multiple Sclerosis

Author(s): Francesca De Vito, Sara Balletta, Silvia Caioli, Alessandra Musella, Livia Guadalupi, Valentina Vanni, Diego Fresegna, Mario Stampanoni Bassi, Luana Gilio, Krizia Sanna, Antonietta Gentile, Antonio Bruno, Ettore Dolcetti, Fabio Buttari, Luigi Pavone, Roberto Furlan, Annamaria Finardi, Emerald Perlas, Eran Hornstein, Diego Centonze* and Georgia Mandolesi

Volume 21, Issue 12, 2023

Published on: 05 April, 2023

Page: [2567 - 2582] Pages: 16

DOI: 10.2174/1570159X21666230404103914

Price: $65

Abstract

Background: TNF-dependent synaptotoxicity contributes to the neuronal damage occurring in patients with Multiple Sclerosis (pwMS) and its mouse model Experimental Autoimmune Encephalomyelitis (EAE). Here, we investigated miR-142-3p, a synaptotoxic microRNA induced by inflammation in EAE and MS, as a potential downstream effector of TNF signalling.

Methods: Electrophysiological recordings, supported by molecular, biochemical and histochemical analyses, were performed to explore TNF-synaptotoxicity in the striatum of EAE and healthy mice. MiR-142 heterozygous (miR-142 HE) mice and/or LNA-anti miR-142-3p strategy were used to verify the TNF-miR-142-3p axis hypothesis. The cerebrospinal fluid (CSF) of 151 pwMS was analysed to evaluate possible correlation between TNF and miR-142-3p levels and their impact on clinical parameters (e.g. progression index (PI), age-related clinical severity (gARMSS)) and MRI measurements at diagnosis (T0).

Results: High levels of TNF and miR-142-3p were detected in both EAE striatum and MS-CSF. The TNF-dependent glutamatergic alterations were prevented in the inflamed striatum of EAE miR-142 HE mice. Accordingly, TNF was ineffective in healthy striatal slices incubated with LNA-anti miR- 142-3p. However, both preclinical and clinical data did not validate the TNF-miR-142-3p axis hypothesis, suggesting a permissive neuronal role of miR-142-3p on TNF-signalling. Clinical data showed a negative impact of each molecule on disease course and/or brain lesions and unveiled that their high levels exert a detrimental synergistic effect on disease activity, PI and white matter lesion volume.

Conclusion: We propose miR-142-3p as a critical modulator of TNF-mediated neuronal toxicity and suggest a detrimental synergistic action of these molecules on MS pathology.

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[1]
Filippi, M.; Bar-Or, A.; Piehl, F.; Preziosa, P.; Solari, A.; Vukusic, S.; Rocca, M.A. Multiple sclerosis. Nat. Rev. Dis. Primers, 2018, 4(1), 43.
[http://dx.doi.org/10.1038/s41572-018-0041-4] [PMID: 30410033]
[2]
Reich, D.S.; Lucchinetti, C.F.; Calabresi, P.A. Multiple sclerosis. N. Engl. J. Med., 2018, 378(2), 169-180.
[http://dx.doi.org/10.1056/NEJMra1401483] [PMID: 29320652]
[3]
Magliozzi, R.; Pezzini, F.; Pucci, M.; Rossi, S.; Facchiano, F.; Marastoni, D.; Montagnana, M.; Lippi, G.; Reynolds, R.; Calabrese, M. Changes in cerebrospinal fluid balance of TNF and TNF receptors in naïve multiple sclerosis patients: Early involvement in compartmentalised intrathecal inflammation. Cells, 2021, 10(7), 1712.
[http://dx.doi.org/10.3390/cells10071712] [PMID: 34359880]
[4]
Calabrese, M.; Magliozzi, R.; Ciccarelli, O.; Geurts, J.J.G.; Reynolds, R.; Martin, R. Exploring the origins of grey matter damage in multiple sclerosis. Nat. Rev. Neurosci., 2015, 16(3), 147-158.
[http://dx.doi.org/10.1038/nrn3900] [PMID: 25697158]
[5]
Michailidou, I.; Willems, J.G.P.; Kooi, E.J.; van Eden, C.; Gold, S.M.; Geurts, J.J.G.; Baas, F.; Huitinga, I.; Ramaglia, V. Complement C1q-C3-associated synaptic changes in multiple sclerosis hippocampus. Ann. Neurol., 2015, 77(6), 1007-1026.
[http://dx.doi.org/10.1002/ana.24398] [PMID: 25727254]
[6]
Di Filippo, M.; Portaccio, E.; Mancini, A.; Calabresi, P. Multiple sclerosis and cognition: Synaptic failure and network dysfunction. Nat. Rev. Neurosci., 2018, 19(10), 599-609.
[http://dx.doi.org/10.1038/s41583-018-0053-9] [PMID: 30158590]
[7]
Mandolesi, G.; Gentile, A.; Musella, A.; Fresegna, D.; De Vito, F.; Bullitta, S.; Sepman, H.; Marfia, G.A.; Centonze, D. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat. Rev. Neurol., 2015, 11(12), 711-724.
[http://dx.doi.org/10.1038/nrneurol.2015.222] [PMID: 26585978]
[8]
Bellingacci, L.; Mancini, A.; Gaetani, L.; Tozzi, A.; Parnetti, L.; Di Filippo, M. Synaptic dysfunction in multiple sclerosis: A red thread from inflammation to network disconnection. Int. J. Mol. Sci., 2021, 22(18), 9753.
[http://dx.doi.org/10.3390/ijms22189753] [PMID: 34575917]
[9]
Ribeiro, C.M.; Oliveira, S.R.; Alfieri, D.F.; Flauzino, T.; Kaimen-Maciel, D.R.; Simão, A.N.C.; Maes, M.; Reiche, E.M.V. Tumor necrosis factor alpha (TNF-α) and its soluble receptors are associated with disability, disability progression and clinical forms of multiple sclerosis. Inflamm. Res., 2019, 68(12), 1049-1059.
[http://dx.doi.org/10.1007/s00011-019-01286-0] [PMID: 31559449]
[10]
James, R.E.; Schalks, R.; Browne, E.; Eleftheriadou, I.; Munoz, C.P.; Mazarakis, N.D.; Reynolds, R. Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration. Acta Neuropathol. Commun., 2020, 8(1), 66.
[http://dx.doi.org/10.1186/s40478-020-00938-1] [PMID: 32398070]
[11]
Picon, C.; Jayaraman, A.; James, R.; Beck, C.; Gallego, P.; Witte, M.E.; van Horssen, J.; Mazarakis, N.D.; Reynolds, R. Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter. Acta Neuropathol., 2021, 141(4), 585-604.
[http://dx.doi.org/10.1007/s00401-021-02274-7] [PMID: 33569629]
[12]
Centonze, D.; Muzio, L.; Rossi, S.; Cavasinni, F.; De Chiara, V.; Bergami, A.; Musella, A.; D’Amelio, M.; Cavallucci, V.; Martorana, A.; Bergamaschi, A.; Cencioni, M.T.; Diamantini, A.; Butti, E.; Comi, G.; Bernardi, G.; Cecconi, F.; Battistini, L.; Furlan, R.; Martino, G. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J. Neurosci., 2009, 29(11), 3442-3452.
[http://dx.doi.org/10.1523/JNEUROSCI.5804-08.2009] [PMID: 19295150]
[13]
Haji, N.; Mandolesi, G.; Gentile, A.; Sacchetti, L.; Fresegna, D.; Rossi, S.; Musella, A.; Sepman, H.; Motta, C.; Studer, V.; De Chiara, V.; Bernardi, G.; Strata, P.; Centonze, D. TNF-α-mediated anxiety in a mouse model of multiple sclerosis. Exp. Neurol., 2012, 237(2), 296-303.
[http://dx.doi.org/10.1016/j.expneurol.2012.07.010] [PMID: 22836148]
[14]
Rossi, S.; Motta, C.; Studer, V.; Barbieri, F.; Buttari, F.; Bergami, A.; Sancesario, G.; Bernardini, S.; De Angelis, G.; Martino, G.; Furlan, R.; Centonze, D. Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration. Mult. Scler., 2014, 20(3), 304-312.
[http://dx.doi.org/10.1177/1352458513498128] [PMID: 23886826]
[15]
Mandolesi, G.; De Vito, F.; Musella, A.; Gentile, A.; Bullitta, S.; Fresegna, D.; Sepman, H.; Di Sanza, C.; Haji, N.; Mori, F.; Buttari, F.; Perlas, E.; Ciotti, M.T.; Hornstein, E.; Bozzoni, I.; Presutti, C.; Centonze, D. MiR-142-3p is a key regulator of IL-1β-dependent synaptopathy in neuroinflammation. J. Neurosci., 2017, 37(3), 546-561.
[http://dx.doi.org/10.1523/JNEUROSCI.0851-16.2016] [PMID: 28100738]
[16]
De Vito, F.; Musella, A.; Fresegna, D.; Rizzo, F.R.; Gentile, A.; Stampanoni Bassi, M. MiR-142-3p regulates synaptopathy-driven disease progression in multiple sclerosis Neuropathol. Appl. Neurobiol., 2021.
[PMID: 34490928]
[17]
Mildner, A.; Chapnik, E.; Manor, O.; Yona, S.; Kim, K.W.; Aychek, T.; Varol, D.; Beck, G.; Itzhaki, Z.B.; Feldmesser, E.; Amit, I.; Hornstein, E.; Jung, S. Mononuclear phagocyte miRNome analysis identifies miR-142 as critical regulator of murine dendritic cell homeostasis. Blood, 2013, 121(6), 1016-1027.
[http://dx.doi.org/10.1182/blood-2012-07-445999] [PMID: 23212522]
[18]
Mandolesi, G.; Musella, A.; Gentile, A.; Grasselli, G.; Haji, N.; Sepman, H.; Fresegna, D.; Bullitta, S.; De Vito, F.; Musumeci, G.; Di Sanza, C.; Strata, P.; Centonze, D. Interleukin-1β alters glutamate transmission at purkinje cell synapses in a mouse model of multiple sclerosis. J. Neurosci., 2013, 33(29), 12105-12121.
[http://dx.doi.org/10.1523/JNEUROSCI.5369-12.2013] [PMID: 23864696]
[19]
Kreitzer, A.C. Physiology and pharmacology of striatal neurons. Annu. Rev. Neurosci., 2009, 32(1), 127-147.
[http://dx.doi.org/10.1146/annurev.neuro.051508.135422] [PMID: 19400717]
[20]
Mao, M.; Nair, A.; Augustine, G.J. A novel type of neuron within the dorsal striatum. Front. Neural Circuits, 2019, 13, 32.
[http://dx.doi.org/10.3389/fncir.2019.00032] [PMID: 31164808]
[21]
Mandolesi, G.; Rizzo, F.R.; Balletta, S.; Stampanoni Bassi, M.; Gilio, L.; Guadalupi, L.; Nencini, M.; Moscatelli, A.; Ryan, C.P.; Licursi, V.; Dolcetti, E.; Musella, A.; Gentile, A.; Fresegna, D.; Bullitta, S.; Caioli, S.; Vanni, V.; Sanna, K.; Bruno, A.; Buttari, F.; Castelli, C.; Presutti, C.; De Santa, F.; Finardi, A.; Furlan, R.; Centonze, D.; De Vito, F. The microRNA let-7b-5p is negatively associated with inflammation and disease severity in multiple sclerosis. Cells, 2021, 10(2), 330.
[http://dx.doi.org/10.3390/cells10020330] [PMID: 33562569]
[22]
Rossi, S.; Furlan, R.; Chiara, V.D.; Muzio, L.; Musella, A.; Motta, C.; Studer, V.; Cavasinni, F.; Bernardi, G.; Martino, G.; Cravatt, B.F.; Lutz, B.; Maccarrone, M.; Centonze, D. Cannabinoid CB1 receptors regulate neuronal TNF-α effects in experimental autoimmune encephalomyelitis. Brain Behav. Immun., 2011, 25(6), 1242-1248.
[http://dx.doi.org/10.1016/j.bbi.2011.03.017] [PMID: 21473912]
[23]
Manouchehrinia, A.; Westerlind, H.; Kingwell, E.; Zhu, F.; Carruthers, R.; Ramanujam, R.; Ban, M.; Glaser, A.; Sawcer, S.; Tremlett, H.; Hillert, J. Age related multiple sclerosis severity score: Disability ranked by age. Mult. Scler., 2017, 23(14), 1938-1946.
[http://dx.doi.org/10.1177/1352458517690618] [PMID: 28155580]
[24]
Fresegna, D.; Bullitta, S.; Musella, A.; Rizzo, F.R.; De Vito, F.; Guadalupi, L.; Caioli, S.; Balletta, S.; Sanna, K.; Dolcetti, E.; Vanni, V.; Bruno, A.; Buttari, F.; Stampanoni Bassi, M.; Mandolesi, G.; Centonze, D.; Gentile, A. Re-examining the role of TNF in MS pathogenesis and therapy. Cells, 2020, 9(10), 2290.
[http://dx.doi.org/10.3390/cells9102290] [PMID: 33066433]
[25]
Stellwagen, D.; Beattie, E.C.; Seo, J.Y.; Malenka, R.C. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J. Neurosci., 2005, 25(12), 3219-3228.
[http://dx.doi.org/10.1523/JNEUROSCI.4486-04.2005] [PMID: 15788779]
[26]
Stellwagen, D.; Malenka, R.C. Synaptic scaling mediated by glial TNF-α. Nature, 2006, 440(7087), 1054-1059.
[http://dx.doi.org/10.1038/nature04671] [PMID: 16547515]
[27]
Leonoudakis, D.; Zhao, P.; Beattie, E.C. Rapid tumor necrosis factor alpha-induced exocytosis of glutamate receptor 2-lacking AMPA receptors to extrasynaptic plasma membrane potentiates excitotoxicity. J. Neurosci., 2008, 28(9), 2119-2130.
[http://dx.doi.org/10.1523/JNEUROSCI.5159-07.2008] [PMID: 18305246]
[28]
Lewitus, G.M.; Pribiag, H.; Duseja, R.; St-Hilaire, M.; Stellwagen, D. An adaptive role of TNFα in the regulation of striatal synapses. J. Neurosci., 2014, 34(18), 6146-6155.
[http://dx.doi.org/10.1523/JNEUROSCI.3481-13.2014] [PMID: 24790185]
[29]
Rizzo, F.R.; Musella, A.; De Vito, F.; Fresegna, D.; Bullitta, S.; Vanni, V.; Guadalupi, L.; Stampanoni Bassi, M.; Buttari, F.; Mandolesi, G.; Centonze, D.; Gentile, A. Tumor necrosis factor and interleukin-1 β modulate synaptic plasticity during neuroinflammation. Neural Plast., 2018, 2018, 1-12.
[http://dx.doi.org/10.1155/2018/8430123] [PMID: 29861718]
[30]
Olmos, G.; Lladó, J. Tumor necrosis factor alpha: A link between neuroinflammation and excitotoxicity. Mediators Inflamm., 2014, 2014, 1-12.
[http://dx.doi.org/10.1155/2014/861231] [PMID: 24966471]
[31]
Musella, A.; Mandolesi, G.; Mori, F.; Gentile, A.; Centonze, D. Linking synaptopathy and gray matter damage in multiple sclerosis. Mult. Scler., 2016, 22(2), 146-149.
[http://dx.doi.org/10.1177/1352458515581875] [PMID: 25921048]
[32]
Gentile, A.; De Vito, F.; Fresegna, D.; Rizzo, F.R.; Bullitta, S.; Guadalupi, L.; Vanni, V.; Buttari, F.; Stampanoni, B.M.; Leuti, A.; Chiurchiù, V.; Marfia, G.A.; Mandolesi, G.; Centonze, D.; Musella, A. Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons. Neuropathol. Appl. Neurobiol., 2020, 46(2), 160-170.
[http://dx.doi.org/10.1111/nan.12569] [PMID: 31125471]
[33]
Zunke, F.; Rose-John, S. The shedding protease ADAM17: Physiology and pathophysiology. Biochim. Biophys. Acta Mol. Cell Res., 2017, 1864(11), 2059-2070.
[http://dx.doi.org/10.1016/j.bbamcr.2017.07.001] [PMID: 28705384]
[34]
Cho, R.W.; Park, J.M.; Wolff, S.B.E.; Xu, D.; Hopf, C.; Kim, J.; Reddy, R.C.; Petralia, R.S.; Perin, M.S.; Linden, D.J.; Worley, P.F. mGluR1/5-dependent long-term depression requires the regulated ectodomain cleavage of neuronal pentraxin NPR by TACE. Neuron, 2008, 57(6), 858-871.
[http://dx.doi.org/10.1016/j.neuron.2008.01.010] [PMID: 18367087]
[35]
Zhao, W.Q.; Santini, F.; Breese, R.; Ross, D.; Zhang, X.D.; Stone, D.J.; Ferrer, M.; Townsend, M.; Wolfe, A.L.; Seager, M.A.; Kinney, G.G.; Shughrue, P.J.; Ray, W.J. Inhibition of calcineurin-mediated endocytosis and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid beta oligomer-induced synaptic disruption. J. Biol. Chem., 2010, 285(10), 7619-7632.
[http://dx.doi.org/10.1074/jbc.M109.057182] [PMID: 20032460]
[36]
Chaudhuri, A.D.; Dastgheyb, R.M.; Yoo, S.W.; Trout, A.; Talbot, C.C., Jr; Hao, H.; Witwer, K.W.; Haughey, N.J. TNFα and IL-1β modify the miRNA cargo of astrocyte shed extracellular vesicles to regulate neurotrophic signaling in neurons. Cell Death Dis., 2018, 9(3), 363.
[http://dx.doi.org/10.1038/s41419-018-0369-4] [PMID: 29507357]
[37]
Bai, Z.; Chen, D.; Wang, L.; Zhao, Y.; Liu, T.; Yu, Y.; Yan, T.; Cheng, Y. Cerebrospinal fluid and blood cytokines as biomarkers for multiple sclerosis: A systematic review and meta-analysis of 226 studies with 13,526 multiple sclerosis patients. Front. Neurosci., 2019, 13, 1026.
[http://dx.doi.org/10.3389/fnins.2019.01026] [PMID: 31636528]
[38]
Rovaris, M.; Barnes, D.; Woodrofe, N.; du Boulay, G.H.; Thorpe, J.W.; Thompson, A.J.; McDonald, W.I.; Miller, D.H. Patterns of disease activity in multiple sclerosis patients: A study with quantitative gadolinium-enhanced brain MRI and cytokine measurement in different clinical subgroups. J. Neurol., 1996, 243(7), 536-542.
[http://dx.doi.org/10.1007/BF00886876] [PMID: 8836944]
[39]
Magliozzi, R.; Howell, O.W.; Nicholas, R.; Cruciani, C.; Castellaro, M.; Romualdi, C.; Rossi, S.; Pitteri, M.; Benedetti, M.D.; Gajofatto, A.; Pizzini, F.B.; Montemezzi, S.; Rasia, S.; Capra, R.; Bertoldo, A.; Facchiano, F.; Monaco, S.; Reynolds, R.; Calabrese, M. Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Ann. Neurol., 2018, 83(4), 739-755.
[http://dx.doi.org/10.1002/ana.25197] [PMID: 29518260]
[40]
Ma, X.; Zhou, J.; Zhong, Y.; Jiang, L.; Mu, P.; Li, Y.; Singh, N.; Nagarkatti, M.; Nagarkatti, P. Expression, regulation and function of microRNAs in multiple sclerosis. Int. J. Med. Sci., 2014, 11(8), 810-818.
[http://dx.doi.org/10.7150/ijms.8647] [PMID: 24936144]

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