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Review

microRNAs: key modulators of disease-modifying therapies in multiple sclerosis

Pancreatic cancer is one of the lethal malignant tumours in the world.In this study, we investigated the CAR T-Cell therapy of pancreatic cancer

ORCID Icon, , , &
Pages 264-279 | Received 10 Dec 2019, Accepted 28 May 2020, Published online: 18 Jun 2020

References

  • Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–558. doi:10.1038/nri3871.
  • Yadav SK, Mindur JE, Ito K, et al. Advances in the immunopathogenesis of multiple sclerosis. Curr Opin Neurol. 2015;28(3):206–219. doi:10.1097/WCO.0000000000000205.
  • Garg N, Smith TW. An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain Behav. 2015;5(9):e00362. doi:10.1002/brb3.362.
  • Cheng Y, Sun L, Xie Z, et al. Diversity of immune cell types in multiple sclerosis and its animal model: pathological and therapeutic implications. J Neurosci Res. 2017;95(10):1973–1983. doi:10.1002/jnr.24023.
  • Grossman I, Knappertz V, Laifenfeld D, et al. Pharmacogenomics strategies to optimize treatments for multiple sclerosis: insights from clinical research. Prog Neurobiol. 2017;152:114–130. doi:10.1016/j.pneurobio.2016.02.001.
  • Gasperini C, Prosperini L, Tintoré M, et al. Unraveling treatment response in multiple sclerosis: a clinical and MRI challenge. Neurology. 2019;92(4):180–192. doi:10.1212/WNL.0000000000006810.
  • Harris VK, Sadiq SA. Biomarkers of therapeutic response in multiple sclerosis: current status. Mol Diagn Ther. 2014;18(6):605–617. doi:10.1007/s40291-014-0117-0.
  • Nadeem A, Ashraf MR, Javed M, et al. Review - MicroRNAs: a new paradigm towards mechanistic insight of diseases. Pak J Pharm Sci. 2018;31(5):2017–2026.
  • Hashimoto Y, Akiyama Y, Yuasa Y. Multiple-to-multiple relationships between microRNAs and target genes in gastric cancer. PLoS One. 2013;8(5):e62589doi:10.1371/journal.pone.0062589.
  • Anglicheau D, Muthukumar T, Suthanthiran M. MicroRNAs: small RNAs with big effects. Transplantation. 2010;90(2):105–112. doi:10.1097/TP.0b013e3181e913c2.
  • Zhang W, Dolan ME. The emerging role of microRNAs in drug responses. Curr Opin Mol Ther. 2010;12(6):695–702.
  • Waschbisch A, Atiya M, Linker RA, et al. Glatiramer acetate treatment normalizes deregulated microRNA expression in relapsing remitting multiple sclerosis. PLoS One. 2011;6(9):e24604. doi:10.1371/journal.pone.0024604.
  • Thamilarasan M, Hecker M, Goertsches RH, et al. Glatiramer acetate treatment effects on gene expression in monocytes of multiple sclerosis patients. J Neuroinflammation. 2013;10:126. doi:10.1186/1742-2094-10-126.
  • Singh J, Deshpande M, Suhail H, et al. Targeted stage-specific inflammatory microRNA profiling in urine during disease progression in experimental autoimmune encephalomyelitis: markers of disease progression and drug response. J Neuroimmune Pharmacol. 2016;11(1):84–97. doi:10.1007/s11481-015-9630-0.
  • Sievers C, Meira M, Hoffmann F, et al. Altered microRNA expression in B lymphocytes in multiple sclerosis: towards a better understanding of treatment effects. Clin Immunol. 2012;144(1):70–79. doi:10.1016/j.clim.2012.04.002.
  • Ingwersen J, Menge T, Wingerath B, et al. Natalizumab restores aberrant miRNA expression profile in multiple sclerosis and reveals a critical role for miR-20b. Ann Clin Transl Neurol. 2015;2(1):43–55. doi:10.1002/acn3.152.
  • Munoz-Culla M, Irizar H, Castillo-Trivino T, et al. Blood miRNA expression pattern is a possible risk marker for natalizumab-associated progressive multifocal leukoencephalopathy in multiple sclerosis patients. Mult Scler. 2014;20(14):1851–1859. doi:10.1177/1352458514534513.
  • Meira M, Sievers C, Hoffmann F, et al. MiR-126: a novel route for natalizumab action? Mult Scler. 2014;20(10):1363–1370. doi:10.1177/1352458514524998.
  • Meira M, Sievers C, Hoffmann F, et al. Unraveling natalizumab effects on deregulated miR-17 expression in CD4+ T cells of patients with relapsing-remitting multiple sclerosis. J Immunol Res. 2014;2014:897249. doi:10.1155/2014/897249.
  • Michell-Robinson MA, Moore CS, Healy LM, et al. Effects of fumarates on circulating and CNS myeloid cells in multiple sclerosis. Ann Clin Transl Neurol. 2016;3(1):27–41. doi:10.1002/acn3.270.
  • Mameli G, Arru G, Caggiu E, et al. Natalizumab therapy modulates miR-155, miR-26a and proinflammatory cytokine expression in MS patients. PLoS One. 2016;11(6):e0157153. doi:10.1371/journal.pone.0157153.
  • Bergman P, Piket E, Khademi M, et al. Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016;3(3):e219. doi:10.1212/NXI.0000000000000219.
  • Meira M, Sievers C, Hoffmann F, et al. Natalizumab-induced POU2AF1/Spi-B upregulation: a possible route for PML development. Neurol Neuroimmunol Neuroinflamm. 2016;3(3):e223. doi:10.1212/NXI.0000000000000223.
  • Hecker M, Thamilarasan M, Koczan D, et al. MicroRNA expression changes during interferon-beta treatment in the peripheral blood of multiple sclerosis patients. Int J Mol Sci. 2013;14(8):16087–16110. doi:10.3390/ijms140816087.
  • De Felice B, Mondola P, Sasso A, et al. Small non-coding RNA signature in multiple sclerosis patients after treatment with interferon-β. BMC Med Genomics. 2014;7:26. doi:10.1186/1755-8794-7-26.
  • Satoh J-i, Takitani M, Miyoshi J, et al. RNA-Seq data analysis identifies the comprehensive profile of in vivo interferon-β-stimulated genes in multiple sclerosis. Clin Exp Neuroimmunol. 2016;7(1):39–51. doi:10.1111/cen3.12268.
  • Ehtesham N, Khorvash F, Kheirollahi M. miR-145 and miR20a-5p potentially mediate pleiotropic effects of interferon-beta through mitogen-activated protein kinase signaling pathway in multiple sclerosis patients. J Mol Neurosci. 2017;61(1):16–24. doi:10.1007/s12031-016-0851-3.
  • Magner WJ, Weinstock-Guttman B, Rho M, et al. Dicer and microRNA expression in multiple sclerosis and response to interferon therapy. J Neuroimmunol. 2016;292:68–78. doi:10.1016/j.jneuroim.2016.01.009.
  • Potenza N, Mosca N, Mondola P, et al. Human miR-26a-5p regulates the glutamate transporter SLC1A1 (EAAT3) expression. Relevance in multiple sclerosis. Biochim Biophys Acta Mol Basis Dis. 2018;1864(1):317–323. doi:10.1016/j.bbadis.2017.09.024.
  • Manna I, Iaccino E, Dattilo V, et al. Exosome-associated miRNA profile as a prognostic tool for therapy response monitoring in multiple sclerosis patients. FASEB J. 2018;32(8):4241–4246. doi:10.1096/fj.201701533R.
  • Fenoglio C, De Riz M, Pietroboni AM, et al. Effect of fingolimod treatment on circulating miR-15b, miR23a and miR-223 levels in patients with multiple sclerosis. J Neuroimmunol. 2016;299:81–83. doi:10.1016/j.jneuroim.2016.08.017.
  • Friess J, Hecker M, Roch L, et al. Fingolimod alters the transcriptome profile of circulating CD4+ cells in multiple sclerosis. Sci Rep. 2017;7(1):42087. doi:10.1038/srep42087.
  • Eftekharian MM, Komaki A, Mazdeh M, et al. Expression profile of selected MicroRNAs in the peripheral blood of multiple sclerosis patients: a multivariate statistical analysis with ROC curve to find new biomarkers for fingolimod. J Mol Neurosci. 2019;68(1):153–161. doi:10.1007/s12031-019-01294-z.
  • Galloway DA, Williams JB, Moore CS. Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation. Ann Clin Transl Neurol. 2017;4(6):381–391. doi:10.1002/acn3.414.
  • Ntranos A, Ntranos V, Bonnefil V, et al. Fumarates target the metabolic-epigenetic interplay of brain-homing T cells in multiple sclerosis. Brain. 2019;142(3):647–661. doi:10.1093/brain/awy344.
  • Dolati S, Aghebati-Maleki L, Ahmadi M, et al. Nanocurcumin restores aberrant miRNA expression profile in multiple sclerosis, randomized, double-blind, placebo-controlled trial. J Cell Physiol. 2018;233(7):5222–5230. doi:10.1002/jcp.26301.
  • Dolati S, Ahmadi M, Aghebti-Maleki L, et al. Nanocurcumin is a potential novel therapy for multiple sclerosis by influencing inflammatory mediators. Pharmacol Rep. 2018;70(6):1158–1167. doi:10.1016/j.pharep.2018.05.008.
  • Hanieh H, Alzahrani A. MicroRNA-132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti-inflammation: a new Ahr-based exploration. Eur J Immunol. 2013;43(10):2771–2782. doi:10.1002/eji.201343486.
  • Abdullah A, Maged M, Hairul-Islam MI, et al. Activation of aryl hydrocarbon receptor signaling by a novel agonist ameliorates autoimmune encephalomyelitis. PLoS One. 2019;14(4):e0215981. doi:10.1371/journal.pone.0215981.
  • Arruda LC, Lorenzi JC, Sousa AP, et al. Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients. Bone Marrow Transplant. 2015;50(3):380–389. doi:10.1038/bmt.2014.277.
  • Vallelunga A, Berlingieri C, Ragusa M, et al. Physical rehabilitation modulates microRNAs involved in multiple sclerosis: a case report. Clin Case Rep. 2017;5(12):2040–2043. doi:10.1002/ccr3.1100.
  • Rouse M, Rao R, Nagarkatti M, et al. 3,3'-diindolylmethane ameliorates experimental autoimmune encephalomyelitis by promoting cell cycle arrest and apoptosis in activated T cells through microRNA signaling pathways . J Pharmacol Exp Ther. 2014;350(2):341–352. doi:10.1124/jpet.114.214742.
  • Rom S, Dykstra H, Zuluaga-Ramirez V, et al. miR-98 and let-7g* protect the blood-brain barrier under neuroinflammatory conditions. J Cereb Blood Flow Metab. 2015;35(12):1957–1965. doi:10.1038/jcbfm.2015.154.
  • Gandy KAO, Zhang J, Nagarkatti P, et al. Resveratrol (3, 5, 4'-Trihydroxy-trans-Stilbene) attenuates a mouse model of multiple sclerosis by altering the miR-124/sphingosine kinase 1 axis in encephalitogenic T cells in the brain. J Neuroimmune Pharmacol. 2019;14(3):462–477. doi:10.1007/s11481-019-09842-5.
  • Zhao M, Sun D, Guan Y, et al. Disulfiram and diphenhydramine hydrochloride upregulate miR-30a to suppress IL-17-associated autoimmune inflammation. J Neurosci. 2016;36(35):9253–9266. doi:10.1523/JNEUROSCI.4587-15.2016.
  • Mishra MK, Wang J, Keough MB, et al. Laquinimod reduces neuroaxonal injury through inhibiting microglial activation. Ann Clin Transl Neurol. 2014;1(6):409–422. doi:10.1002/acn3.67.
  • Otaegui D, Baranzini SE, Armananzas R, et al. Differential micro RNA expression in PBMC from multiple sclerosis patients. PLoS One. 2009;4(7):e6309doi:10.1371/journal.pone.0006309.
  • Li D, Li YP, Li YX, et al. Effect of regulatory network of exosomes and microRNAs on neurodegenerative diseases. Chin Med J. 2018;131(18):2216–2225. doi:10.4103/0366-6999.240817.
  • Marco Ramassone DM, Pagotto A, Anastasiadou S, et al. MicroRNAs in autoimmunity and hematological malignancies. Int J Mol Sci. 2018;19(10):E3139.
  • To KK, Tong CW, Wu M, et al. MicroRNAs in the prognosis and therapy of colorectal cancer: From bench to bedside. World J Gastroenterol. 2018;24(27):2949–2973. doi:10.3748/wjg.v24.i27.2949.
  • Zhou Q, Liu J, Quan J, et al. MicroRNAs as potential biomarkers for the diagnosis of glioma: A systematic review and meta-analysis. Cancer Sci. 2018;109(9):2651–2659. doi:10.1111/cas.13714.
  • Hon KW, Abu N, Ab Mutalib N-S, et al. miRNAs and lncRNAs as predictive biomarkers of response to FOLFOX therapy in colorectal cancer. Front Pharmacol. 2018;9:846.
  • Biswas S. MicroRNAs as therapeutic agents: the future of the battle against cancer. Curr Top Med Chem. 2018;18(30):2544–2554. doi:10.2174/1568026619666181120121830.
  • Keller A, Leidinger P, Steinmeyer F, et al. Comprehensive analysis of microRNA profiles in multiple sclerosis including next-generation sequencing. Mult Scler. 2014;20(3):295–303. doi:10.1177/1352458513496343.
  • Sondergaard HB, Hesse D, Krakauer M, et al. Differential microRNA expression in blood in multiple sclerosis. Mult Scler. 2013;19(14):1849–1857. doi:10.1177/1352458513490542.
  • Sanders KA, Benton MC, Lea RA, et al. Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4+ T cells. Clin Epigenet. 2016;8(1):87. doi:10.1186/s13148-016-0253-y.
  • Lindberg RL, Hoffmann F, Mehling M, et al. Altered expression of miR-17-5p in CD4+ lymphocytes of relapsing-remitting multiple sclerosis patients. Eur J Immunol. 2010;40(3):888–898. doi:10.1002/eji.200940032.
  • De Santis G, Ferracin M, Biondani A, et al. Altered miRNA expression in T regulatory cells in course of multiple sclerosis. J Neuroimmunol. 2010;226(1–2):165–171. doi:10.1016/j.jneuroim.2010.06.009.
  • Hoye ML, Archambault AS, Gordon TM, et al. MicroRNA signature of central nervous system-infiltrating dendritic cells in an animal model of multiple sclerosis. Immunology. 2018;155(1):112–122. doi:10.1111/imm.12934.
  • Groen K, Maltby VE, Lea RA, et al. Erythrocyte microRNA sequencing reveals differential expression in relapsing-remitting multiple sclerosis. BMC Med Genomics. 2018;11(1):48. doi:10.1186/s12920-018-0365-7.
  • Junker A, Krumbholz M, Eisele S, et al. MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain. 2009;132(Pt 12):3342–3352. doi:10.1093/brain/awp300.
  • Gandhi R, Healy B, Gholipour T, et al. Circulating microRNAs as biomarkers for disease staging in multiple sclerosis. Ann Neurol. 2013;73(6):729–740. doi:10.1002/ana.23880.
  • Regev K, Healy BC, Paul A, et al. Identification of MS-specific serum miRNAs in an international multicenter study. Neurol Neuroimmunol Neuroinflamm. 2018;5(5):e491doi:10.1212/NXI.0000000000000491.
  • Haghikia A, Haghikia A, Hellwig K, et al. Regulated microRNAs in the CSF of patients with multiple sclerosis: a case-control study. Neurology. 2012;79(22):2166–2170. doi:10.1212/WNL.0b013e3182759621.
  • Piket E, Zheleznyakova GY, Kular L, et al. Small non-coding RNAs as important players, biomarkers and therapeutic targets in multiple sclerosis: a comprehensive overview. J Autoimmun. 2019;101:17–25. doi:10.1016/j.jaut.2019.04.002.
  • Lazibat I, Rubinic Majdak M, Zupanic S. Multiple sclerosis: new aspects of immunopathogenesis. Acta Clin Croat. 2018;57(2):352–361. doi:10.20471/acc.2018.57.02.17.
  • Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity. 2009;30(5):626–635. doi:10.1016/j.immuni.2009.05.002.
  • Tao JH, Cheng M, Tang JP, et al. Foxp3, regulatory T cell, and autoimmune diseases. Inflammation. 2017;40(1):328–339. doi:10.1007/s10753-016-0470-8.
  • Liston A, Lu L-F, O'Carroll D, et al. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med. 2008;205(9):1993–2004. doi:10.1084/jem.20081062.
  • Chong MMW, Rasmussen JP, Rudensky AY, et al. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med. 2008;205(9):2005–2017. doi:10.1084/jem.20081219.
  • Hippen KL, Loschi M, Nicholls J, et al. Effects of MicroRNA on regulatory T Cells and implications for adoptive cellular therapy to ameliorate graft-versus-host disease. Front Immunol. 2018;9:57. doi:10.3389/fimmu.2018.00057.
  • Cruz LO, Hashemifar SS, Wu C-J, et al. Excessive expression of miR-27 impairs Treg-mediated immunological tolerance. J Clin Invest. 2017;127(2):530–542. doi:10.1172/JCI88415.
  • Jiang S, Li C, Olive V, et al. Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation. Blood. 2011;118(20):5487–5497. doi:10.1182/blood-2011-05-355644.
  • Yang HY, Barbi J, Wu CY, et al. MicroRNA-17 modulates regulatory T cell function by targeting co-regulators of the Foxp3 transcription factor. Immunity. 2016;45(1):83–93. doi:10.1016/j.immuni.2016.06.022.
  • Fayyad-Kazan H, Rouas R, Fayyad-Kazan M, et al. MicroRNA profile of circulating CD4-positive regulatory T cells in human adults and impact of differentially expressed microRNAs on expression of two genes essential to their function. J Biol Chem. 2012;287(13):9910–9922. doi:10.1074/jbc.M111.337154.
  • Heyn J, Luchting B, Hinske LC, et al. miR-124a and miR-155 enhance differentiation of regulatory T cells in patients with neuropathic pain. J Neuroinflamm. 2016;13(1):248. doi:10.1186/s12974-016-0712-6.
  • Lu Y, Gao J, Zhang S, et al. miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg). Cell Death Dis. 2018;9(3):290. doi:10.1038/s41419-018-0298-2.
  • Zhou Q, Haupt S, Prots I, et al. miR-142-3p is involved in CD25+ CD4 T cell proliferation by targeting the expression of glycoprotein A repetitions predominant. J Immunol. 2013;190(12):6579–6588. doi:10.4049/jimmunol.1202993.
  • Gao J, Gu J, Pan X, et al. Blockade of miR-142-3p promotes anti-apoptotic and suppressive function by inducing KDM6A-mediated H3K27me3 demethylation in induced regulatory T cells. Cell Death Dis. 2019;10(5):332. doi:10.1038/s41419-019-1565-6.
  • Huang B, Zhao J, Lei Z, et al. miR-142-3p restricts cAMP production in CD4 + CD25- T cells and CD4 + CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep. 2009;10(2):180–185. doi:10.1038/embor.2008.224.
  • Keller A, Leidinger P, Lange J, et al. Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls. PLoS One. 2009;4(10):e7440. doi:10.1371/journal.pone.0007440.
  • Gerrard B, Singh V, Babenko O, et al. Chronic mild stress exacerbates severity of experimental autoimmune encephalomyelitis in association with altered non-coding RNA and metabolic biomarkers. Neuroscience. 2017;359:299–307. doi:10.1016/j.neuroscience.2017.07.033.
  • Raphael I, Nalawade S, Eagar TN, et al. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74(1):5–17. doi:10.1016/j.cyto.2014.09.011.
  • Paraboschi EM, Solda G, Gemmati D, et al. Genetic association and altered gene expression of mir-155 in multiple sclerosis patients. Int J Mol Sci. 2011;12(12):8695–8712. doi:10.3390/ijms12128695.
  • Zhang J, Cheng Y, Cui W, et al. MicroRNA-155 modulates Th1 and Th17 cell differentiation and is associated with multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol. 2014;266(1–2):56–63. doi:10.1016/j.jneuroim.2013.09.019.
  • Alivernini S, Gremese E, McSharry C, et al. MicroRNA-155-at the critical interface of innate and adaptive immunity in arthritis. Front Immunol. 2017;8:1932. doi:10.3389/fimmu.2017.01932.
  • Smith KM, Guerau-de-Arellano M, Costinean S, et al. miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis. J Immunol. 2012;189(4):1567–1576. doi:10.4049/jimmunol.1103171.
  • Liston A, Papadopoulou AS, Danso-Abeam D, et al. MicroRNA-29 in the adaptive immune system: setting the threshold. Cell Mol Life Sci. 2012;69(21):3533–3541. doi:10.1007/s00018-012-1124-0.
  • Guerau-de-Arellano M, Smith KM, Godlewski J, et al. Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity. Brain. 2011;134(Pt 12):3578–3589. doi:10.1093/brain/awr262.
  • Jadidi-Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol. 2011;74(1):1–13. doi:10.1111/j.1365-3083.2011.02536.x.
  • Li Y-F, Zhang S-X, Ma X-W, et al. Levels of peripheral Th17 cells and serum Th17-related cytokines in patients with multiple sclerosis: a meta-analysis . Mult Scler Relat Disord. 2017;18:20–25. doi:10.1016/j.msard.2017.09.003.
  • Hu R, Huffaker TB, Kagele DA, et al. MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression. J Immunol. 2013;190(12):5972–5980. doi:10.4049/jimmunol.1300351.
  • Escobar TM, Kanellopoulou C, Kugler DG, et al. miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression. Immunity. 2014;40(6):865–879. doi:10.1016/j.immuni.2014.03.014.
  • Du C, Liu C, Kang J, et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol. 2009;10(12):1252–1259. doi:10.1038/ni.1798.
  • Zhu E, Wang X, Zheng B, et al. miR-20b suppresses Th17 differentiation and the pathogenesis of experimental autoimmune encephalomyelitis by targeting RORγt and STAT3. J Immunol. 2014;192(12):5599–5609. doi:10.4049/jimmunol.1303488.
  • Park SY, Lee JH, Ha M, et al. miR-29 miRNAs activate p53 by targeting p85 alpha and CDC42. Nat Struct Mol Biol. 2009;16(1):23–29. doi:10.1038/nsmb.1533.
  • Murugaiyan G, da Cunha AP, Ajay AK, et al. MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J Clin Invest. 2015;125(3):1069–1080. doi:10.1172/JCI74347.
  • Montoya MM, Maul J, Singh PB, et al. A distinct inhibitory function for miR-18a in Th17 cell differentiation. J Immunol. 2017;199(2):559–569. doi:10.4049/jimmunol.1700170.
  • Liu SQ, Jiang S, Li C, et al. miR-17-92 cluster targets phosphatase and tensin homology and Ikaros Family Zinc Finger 4 to promote TH17-mediated inflammation. J Biol Chem. 2014;289(18):12446–12456. doi:10.1074/jbc.M114.550723.
  • Qu X, Zhou J, Wang T, et al. MiR-30a inhibits Th17 differentiation and demyelination of EAE mice by targeting the IL-21R. Brain Behav Immun. 2016;57:193–199. doi:10.1016/j.bbi.2016.03.016.
  • Negron A, Robinson RR, Stüve O, et al. The role of B cells in multiple sclerosis: Current and future therapies. Cell Immunol. 2019;339:10–23. doi:10.1016/j.cellimm.2018.10.006.
  • Fan X, Lin C, Han J, et al. Follicular helper CD4+ T cells in human neuroautoimmune diseases and their animal models. Mediators Inflamm. 2015;2015:638968. doi:10.1155/2015/638968.
  • Romme Christensen J, Bornsen L, Ratzer R, et al. Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression. PLoS One. 2013;8(3):e57820. doi:10.1371/journal.pone.0057820.
  • Hu R, Kagele DA, Huffaker TB, et al. miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity. 2014;41(4):605–619. doi:10.1016/j.immuni.2014.09.015.
  • Thai TH, Calado DP, Casola S, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316(5824):604–608. doi:10.1126/science.1141229.
  • Boldin MP, Taganov KD, Rao DS, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med. 2011;208(6):1189–1201. doi:10.1084/jem.20101823.
  • Pratama A, Srivastava M, Williams NJ, et al. MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. Nat Commun. 2015;6:6436. doi:10.1038/ncomms7436.
  • Cho S, Lee HM, Yu IS, et al. Differential cell-intrinsic regulations of germinal center B and T cells by miR-146a and miR-146b. Nat Commun. 2018;9(1):2757. doi:10.1038/s41467-018-05196-3.
  • Baumjohann D, Kageyama R, Clingan JM, et al. The microRNA cluster miR-17 ∼ 92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat Immunol. 2013;14(8):840–848. doi:10.1038/ni.2642.
  • Kang SG, Liu WH, Lu P, et al. MicroRNAs of the miR-17 ∼ 92 family are critical regulators of T(FH) differentiation. Nat Immunol. 2013;14(8):849–857. doi:10.1038/ni.2648.
  • Kabba JA, Xu Y, Christian H, et al. Microglia: housekeeper of the central nervous system. Cell Mol Neurobiol. 2018;38(1):53–71. doi:10.1007/s10571-017-0504-2.
  • Chu F, Shi M, Zheng C, et al. The roles of macrophages and microglia in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol. 2018;318:1–7. doi:10.1016/j.jneuroim.2018.02.015.
  • O'Connell RM, Taganov KD, Boldin MP, et al. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA. 2007;104(5):1604–1609. doi:10.1073/pnas.0610731104.
  • Martinez-Nunez RT, Louafi F, Sanchez-Elsner T. The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor alpha1 (IL13Ralpha1). J Biol Chem. 2011;286(3):1786–1794. doi:10.1074/jbc.M110.169367.
  • O'Connell RM, Chaudhuri AA, Rao DS, et al. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci USA. 2009;106(17):7113–7118. doi:10.1073/pnas.0902636106.
  • Cardoso AL, Guedes JR, Pereira de Almeida L, et al. miR-155 modulates microglia-mediated immune response by down-regulating SOCS-1 and promoting cytokine and nitric oxide production. Immunology. 2012;135(1):73–88. doi:10.1111/j.1365-2567.2011.03514.x.
  • Woodbury ME, Freilich RW, Cheng CJ, et al. miR-155 is essential for inflammation-induced hippocampal neurogenic dysfunction. J Neurosci. 2015;35(26):9764–9781. doi:10.1523/JNEUROSCI.4790-14.2015.
  • Yan L, Lee S, Lazzaro DR, et al. Single and compound knock-outs of MicroRNA (miRNA)-155 and its angiogenic gene target CCN1 in mice alter vascular and neovascular growth in the retina via resident microglia. J Biol Chem. 2015;290(38):23264–23281. doi:10.1074/jbc.M115.646950.
  • Moore CS, Rao VTS, Durafourt BA, et al. miR-155 as a multiple sclerosis-relevant regulator of myeloid cell polarization. Ann Neurol. 2013;74(5):709–720. doi:10.1002/ana.23967.
  • Chen L, Dong R, Lu Y, et al. MicroRNA-146a protects against cognitive decline induced by surgical trauma by suppressing hippocampal neuroinflammation in mice. Brain Behav Immun. 2019;78:188–201. doi:10.1016/j.bbi.2019.01.020.
  • Taganov KD, Boldin MP, Chang KJ, et al. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA. 2006;103(33):12481–12486. doi:10.1073/pnas.0605298103.
  • Marangon D, Raffaele S, Fumagalli M, et al. MicroRNAs change the games in central nervous system pharmacology. Biochem Pharmacol. 2019;168:162–172. doi:10.1016/j.bcp.2019.06.019.
  • Thounaojam MC, Kaushik DK, Kundu K, et al. MicroRNA-29b modulates Japanese encephalitis virus-induced microglia activation by targeting tumor necrosis factor alpha-induced protein 3. J Neurochem. 2014;129(1):143–154. doi:10.1111/jnc.12609.
  • Xie N, Cui H, Banerjee S, et al. miR-27a regulates inflammatory response of macrophages by targeting IL-10. J Immunol. 2014;193(1):327–334. doi:10.4049/jimmunol.1400203.
  • Thulin P, Wei T, Werngren O, et al. MicroRNA-9 regulates the expression of peroxisome proliferator-activated receptor δ in human monocytes during the inflammatory response. Int J Mol Med. 2013;31(5):1003–1010. doi:10.3892/ijmm.2013.1311.
  • Sheedy FJ, Palsson-McDermott E, Hennessy EJ, et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol. 2010;11(2):141–147. doi:10.1038/ni.1828.
  • Barnett RE, Conklin DJ, Ryan L, et al. Anti-inflammatory effects of miR-21 in the macrophage response to peritonitis. J Leukoc Biol. 2016;99(2):361–371. doi:10.1189/jlb.4A1014-489R.
  • Su W, Hopkins S, Nesser NK, et al. The p53 transcription factor modulates microglia behavior through microRNA-dependent regulation of c-Maf. J Immunol. 2014;192(1):358–366. doi:10.4049/jimmunol.1301397.
  • Xie X, Peng L, Zhu J, et al. miR-145-5p/Nurr1/TNF-α signaling-induced microglia activation regulates neuron injury of acute cerebral ischemic/reperfusion in rats. Front Mol Neurosci. 2017;10:383. doi:10.3389/fnmol.2017.00383.
  • Hamzei Taj S, Kho W, Aswendt M, et al. Dynamic modulation of microglia/macrophage polarization by miR-124 after focal cerebral ischemia. J Neuroimmune Pharmacol. 2016;11(4):733–748. doi:10.1007/s11481-016-9700-y.
  • Ponomarev ED, Veremeyko T, Barteneva N, et al. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway. Nat Med. 2011;17(1):64–70. doi:10.1038/nm.2266.
  • Svahn AJ, Giacomotto J, Graeber MB, et al. miR-124 Contributes to the functional maturity of microglia. Dev Neurobiol. 2016;76(5):507–518. doi:10.1002/dneu.22328.
  • Yu A, Zhang T, Duan H, et al. MiR-124 contributes to M2 polarization of microglia and confers brain inflammatory protection via the C/EBP-α pathway in intracerebral hemorrhage. Immunol Lett. 2017;182:1–11. doi:10.1016/j.imlet.2016.12.003.
  • Ma C, Li Y, Li M, et al. microRNA-124 negatively regulates TLR signaling in alveolar macrophages in response to mycobacterial infection. Mol Immunol. 2014;62(1):150–158. doi:10.1016/j.molimm.2014.06.014.
  • Veremeyko T, Siddiqui S, Sotnikov I, et al. IL-4/IL-13-dependent and independent expression of miR-124 and its contribution to M2 phenotype of monocytic cells in normal conditions and during allergic inflammation. PLoS One. 2013;8(12):e81774. doi:10.1371/journal.pone.0081774.
  • Sun Y, Li Q, Gui H, et al. MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines. Cell Res. 2013;23(11):1270–1283. doi:10.1038/cr.2013.116.
  • Liebner S, Dijkhuizen RM, Reiss Y, et al. Functional morphology of the blood-brain barrier in health and disease. Acta Neuropathol. 2018;135(3):311–336. doi:10.1007/s00401-018-1815-1.
  • Ortiz GG, Pacheco-Moises FP, Macias-Islas MA, et al. Role of the blood-brain barrier in multiple sclerosis. Arch Med Res. 2014;45(8):687–697. doi:10.1016/j.arcmed.2014.11.013.
  • Lopez-Ramirez MA, Wu D, Pryce G, et al. MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation. FASEB J. 2014;28(6):2551–2565. doi:10.1096/fj.13-248880.
  • Cascio S, D'Andrea A, Ferla R, et al. miR-20b modulates VEGF expression by targeting HIF-1 alpha and STAT3 in MCF-7 breast cancer cells. J Cell Physiol. 2010;224(1):242–249. doi:10.1002/jcp.22126.
  • Argaw AT, Gurfein BT, Zhang Y, et al. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc Natl Acad Sci USA. 2009;106(6):1977–1982. doi:10.1073/pnas.0808698106.
  • Martinelli-Boneschi F, Fenoglio C, Brambilla P, et al. MicroRNA and mRNA expression profile screening in multiple sclerosis patients to unravel novel pathogenic steps and identify potential biomarkers. Neurosci Lett. 2012;508(1):4–8. doi:10.1016/j.neulet.2011.11.006.
  • Aung LL, Mouradian MM, Dhib-Jalbut S, et al. MMP-9 expression is increased in B lymphocytes during multiple sclerosis exacerbation and is regulated by microRNA-320a. J Neuroimmunol. 2015;278:185–189. doi:10.1016/j.jneuroim.2014.11.004.
  • Kalani A, Kamat PK, Familtseva A, et al. Role of microRNA29b in blood-brain barrier dysfunction during hyperhomocysteinemia: an epigenetic mechanism. J Cereb Blood Flow Metab. 2014;34(7):1212–1222. doi:10.1038/jcbfm.2014.74.
  • Macchi B, Marino-Merlo F, Nocentini U, et al. Role of inflammation and apoptosis in multiple sclerosis: comparative analysis between the periphery and the central nervous system. J Neuroimmunol. 2015;287:80–87. doi:10.1016/j.jneuroim.2015.08.016.
  • Wang S, Wan X, Ruan Q. The microRNA-21 in autoimmune diseases. Int J Mol Sci. 2016;17(6):864. doi:10.3390/ijms17060864.
  • Ventura A, Young AG, Winslow MM, et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008;132(5):875–886. doi:10.1016/j.cell.2008.02.019.
  • Yang Q, Pan W, Qian L. Identification of the miRNA-mRNA regulatory network in multiple sclerosis. Neurol Res. 2017;39(2):142–151. doi:10.1080/01616412.2016.1250857.
  • Lorenzi JC, Brum DG, Zanette DL, et al. miR-15a and 16-1 are downregulated in CD4+ T cells of multiple sclerosis relapsing patients. Int J Neurosci. 2012;122(8):466–471. doi:10.3109/00207454.2012.678444.
  • Mandolesi G, De Vito F, Musella A, et al. miR-142-3p is a key regulator of IL-1β-dependent synaptopathy in neuroinflammation. J Neurosci. 2017;37(3):546–561. doi:10.1523/JNEUROSCI.0851-16.2016.
  • Galloway DA, Blandford SN, Berry T, et al. miR-223 promotes regenerative myeloid cell phenotype and function in the demyelinated central nervous system. Glia. 2019;67(5):857–869. doi:10.1002/glia.23576.
  • Morquette B, Juźwik CA, Drake SS, et al. MicroRNA-223 protects neurons from degeneration in experimental autoimmune encephalomyelitis. Brain. 2019;142(10):2979–2995. doi:10.1093/brain/awz245.
  • Li JS, Yao ZX. MicroRNAs: novel regulators of oligodendrocyte differentiation and potential therapeutic targets in demyelination-related diseases. Mol Neurobiol. 2012;45(1):200–212. doi:10.1007/s12035-011-8231-z.
  • Zhang R, Tian A, Wang J, et al. miR26a modulates Th17/T reg balance in the EAE model of multiple sclerosis by targeting IL6. Neuromol Med. 2015;17(1):24–34. doi:10.1007/s12017-014-8335-5.
  • Kumar A, Bhatia HS, de Oliveira AC, et al. microRNA-26a modulates inflammatory response induced by toll-like receptor 4 stimulation in microglia. J Neurochem. 2015;135(6):1189–1202. doi:10.1111/jnc.13364.
  • Liu R, Ma X, Chen L, et al. MicroRNA-15b suppresses Th17 differentiation and is associated with pathogenesis of multiple sclerosis by targeting O-GlcNAc transferase. J Immunol. 2017;198(7):2626–2639. doi:10.4049/jimmunol.1601727.
  • Singh Y, Garden OA, Lang F, et al. MicroRNA-15b/16 enhances the induction of regulatory T cells by regulating the expression of rictor and mTOR. J Immunol. 2015;195(12):5667–5677. doi:10.4049/jimmunol.1401875.
  • Liang X, Xu Z, Yuan M, et al. MicroRNA-16 suppresses the activation of inflammatory macrophages in atherosclerosis by targeting PDCD4. Int J Mol Med. 2016;37(4):967–975. doi:10.3892/ijmm.2016.2497.
  • Nakahama T, Hanieh H, Nguyen NT, et al. Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17-producing T-helper cell differentiation. Proc Natl Acad Sci USA. 2013;110(29):11964–11969. doi:10.1073/pnas.1311087110.
  • Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870–1880. doi:10.1056/NEJMoa1107829.
  • Basnyat P, Virtanen E, Elovaara I, et al. JCPyV microRNA in plasma inversely correlates with JCPyV seropositivity among long-term natalizumab-treated relapsing-remitting multiple sclerosis patients. J Neurovirol. 2017;23(5):734–741. doi:10.1007/s13365-017-0560-x.

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