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miR26a Modulates Th17/Treg Balance in the EAE Model of Multiple Sclerosis by Targeting IL6

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Abstract

A number of different microRNAs (miRNAs) have been implicated in various autoimmune diseases, including multiple sclerosis (MS). T helper (Th)17 and regulatory T cells (Tregs) have likewise been implicated as key players in MS, and a functional imbalance of these cell types is increasingly recognized as a key etiological factor in the disease. Although specific panels of transcription factors and cytokines are known to regulate the Th17/Treg balance, the role of noncoding RNAs remains poorly understood. The inflammatory cytokine, interleukin (IL)6, appears to play a critical role in both the development of the Th17 response and the inhibition of Treg functions. In this research, an IL6-associated miRNA, miR26a, was identified, and its normally downregulated expression was shown to be highly correlated with disease severity in patients suffering from MS as well as in C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE; a well-established animal model of human MS). Using the EAE model system, in vivo silencing of miR26a was found to result in increased expression of Th17-related cytokines and increased severity of EAE, while overexpression of miR26a was found to result in reduced expression of Th17-related cytokines and a milder form of EAE. By contrast, Treg cell-specific transcription factor, Foxp3, was found to be positively correlated with miR26a expression. Finally, miR26a was found to downregulate Th17 and to upregulate Treg cell function through its targeting of IL6. Taken together, our data indicate an important role for miR26a in maintaining the Th17 and Treg cell balance in MS that involves repression of IL6 expression.

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References

  • Ambros, V. (2004). The functions of animal microRNAs. Nature, 431, 350–355.

    Article  CAS  PubMed  Google Scholar 

  • Baecher-Allan, C., & Hafler, D. A. (2004). Suppressor T cells in human diseases. The Journal of Experimental Medicine, 200, 273–276.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Baltimore, D., Boldin, M. P., O’Connell, R. M., Rao, D. S., & Taganov, K. D. (2008). MicroRNAs: New regulators of immune cell development and function. Nature Immunology, 9, 839–845.

    Article  CAS  PubMed  Google Scholar 

  • Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., et al. (2006). Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature, 441, 235–238.

    Article  CAS  PubMed  Google Scholar 

  • Bielekova, B., & Martin, R. (2004). Development of biomarkers in multiple sclerosis. Brain, 127, 1463–1478.

    Article  PubMed  Google Scholar 

  • Chen, X., Howard, O. M., & Oppenheim, J. J. (2007). Pertussis toxin by inducing IL6 promotes the generation of IL17-producing CD4 cells. The Journal of Immunology, 178, 6123–6129.

    Article  CAS  PubMed  Google Scholar 

  • Compston, A., & Coles, A. (2008). Multiple sclerosis. Lancet, 372, 1502–1517.

    Article  CAS  PubMed  Google Scholar 

  • Cox, M. B., Cairns, M. J., Gandhi, K. S., Carroll, A. P., Moscovis, S., Stewart, G., et al. (2010). ANZgene Multiple Sclerosis Genetics Consortium. MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood. PLoS ONE, 5, e12132.

    Article  PubMed Central  PubMed  Google Scholar 

  • Diveu, C., McGeachy, M. J., & Cua, D. J. (2008). Cytokines that regulate autoimmunity. Current Opinion in Immunology, 20, 663–668.

    Article  CAS  PubMed  Google Scholar 

  • Du, C., Liu, C., Kang, J., Zhao, G., Ye, Z., & Huang, S. (2009). MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nature Immunology, 10, 1252–1259.

    Article  CAS  PubMed  Google Scholar 

  • Ehrenstein, M. R., Evans, J. G., Singh, A., Moore, S., Warnes, G., Isenberg, D. A., et al. (2004). Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. The Journal of Experimental Medicine, 200, 277–285.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Haas, J., Hug, A., Viehöver, A., Fritzsching, B., Falk, C. S., Filser, A., et al. (2005). Reduced suppressive effect of CD4 + CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. European Journal of Immunology, 35, 3343–3352.

    Article  CAS  PubMed  Google Scholar 

  • Honardoost, M. A., Kiani-Esfahani, A., Ghaedi, K., Etemadifar, M., & Salehi, M. (2014). miR-326 and miR-26a, two potential markers for diagnosis of relapse and remission phases in patient with relapsing–remitting multiple sclerosis. Gene, 544, 128–133.

    Article  CAS  PubMed  Google Scholar 

  • Huse, J. T., Brennan, C., Hambardzumyan, D., Wee, B., Pena, J., Rouhanifard, S. H., et al. (2009). The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes & Development, 23, 1327–1337.

    Article  CAS  Google Scholar 

  • Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., et al. (2006). The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL17 + T helper cells. Cell, 126, 1121–1133.

    Article  CAS  PubMed  Google Scholar 

  • Ji, J., Shi, J., Budhu, A., Yu, Z., Forgues, M., Roessler, S., et al. (2009). MicroRNA expression, survival, and response to interferon in liver cancer. New England Journal of Medicine, 361, 1437–1447.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jonuleit, H., Schmitt, E., Stassen, M., Tuettenberg, A., Knop, J., & Enk, A. H. (2001). Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. The Journal of Experimental Medicine, 193, 1285–1294.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Junker, A., Krumbholz, M., Eisele, S., Mohan, H., Augstein, F., Bittner, R., et al. (2009a). MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain, 132, 3342–3352.

    Article  PubMed  Google Scholar 

  • Junker, A., Krumbholz, M., Eisele, S., Mohan, H., Augstein, F., Bittner, R., et al. (2009b). MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain, 132, 3342–3352.

    Article  PubMed  Google Scholar 

  • Kebir, H., Ifergan, I., Alvarez, J. I., Bernard, M., Poirier, J., Arbour, N., et al. (2009). Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Annals of Neurology, 66, 390–402.

    Article  CAS  PubMed  Google Scholar 

  • Keller, A., Leidinger, P., Lange, J., Borries, A., Schroers, H., Scheffler, M., et al. (2009). Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls. PLoS ONE, 4, e7440.

    Article  PubMed Central  PubMed  Google Scholar 

  • Kim, H., Huang, W., Jiang, X., Pennicooke, B., Park, P. J., & Johnson, M. D. (2010). Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. Proceedings of the National Academy of Sciences, 107, 2183–2188.

    Article  CAS  Google Scholar 

  • Kota, J., Chivukula, R. R., O’Donnell, K. A., Wentzel, E. A., Montgomery, C. L., Hwang, H. W., et al. (2009). Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell, 37, 1005–1017.

    Article  Google Scholar 

  • Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., et al. (2005). IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. The Journal of Experimental Medicine, 201, 233–240.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lindberg, R. L., Hoffmann, F., Mehling, M., Kuhle, J., & Kappos, L. (2010). Altered expression of miR-17-5p in CD4 + lymphocytes of relapsing-remitting multiple sclerosis patients. European Journal of Immunology, 40, 888–898.

    Article  CAS  PubMed  Google Scholar 

  • Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., et al. (2002). Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Medicine, 8, 500–508.

    Article  CAS  PubMed  Google Scholar 

  • Lorenzi, J. C., Brum, D. G., Zanette, D. L., de Paula Alves Souza, A., Barbuzano, F. G., Dos Santos, A. C., et al. (2012). miR-15a and 16-1 are downregulated in CD4 + T cells of multiple sclerosis relapsing patients. International Journal of Neuroscience, 122, 466–471.

    Article  CAS  PubMed  Google Scholar 

  • Lu, J., Getz, G., Miska, E. A., Alvarez-Saavedra, E., Lamb, J., Peck, D., et al. (2005). MicroRNA expression profiles classify human cancers. Nature, 435, 834–838.

    Article  CAS  PubMed  Google Scholar 

  • Ma, X. T., Zhou, J., Zhong, Y., Jiang, L. I., Mu, P., Li, Y., et al. (2014). Expression, Regulation and Function of MicroRNAs in Multiple Sclerosis. International Journal of Medical Sciences, 11, 810–818.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., et al. (2007). Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science, 317, 256–260.

    Article  CAS  PubMed  Google Scholar 

  • Murugaiyan, G., Beynon, V., Mittal, A., Joller, N., & Weiner, H. L. (2011a). Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. The Journal of Immunology, 187, 2213–2221.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Murugaiyan, G., Beynon, V., Mittal, A., Joller, N., & Weiner, H. L. (2011b). Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. The Journal of Immunology, 187, 2213–2221.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nelson, P. T., Wang, W. X., & Rajeev, B. W. (2008). MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathology, 18, 130–138.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nishihara, M., Ogura, H., Ueda, N., Tsuruoka, M., Kitabayashi, C., Tsuji, F., et al. (2007). IL6–gp130–STAT3 in T cells directs the development of IL17 + Th with a minimum effect on that of Treg in the steady state. International Immunology, 19, 695–702.

    Article  CAS  PubMed  Google Scholar 

  • O’Connell, R. M., Taganov, K. D., Boldin, M. P., Cheng, G., & Baltimore, D. (2007). MicroRNA-155 is induced during the macrophage inflammatory response. Proceedings of the National Academy of Sciences, 104, 1604–1609.

    Article  Google Scholar 

  • O’Connell, R. M., Rao, D. S., Chaudhuri, A. A., & Baltimore, D. (2010). Physiological and pathological roles for microRNAs in the immune system. Nature Reviews Immunology, 10, 111–122.

    Article  PubMed  Google Scholar 

  • Otaegui, D., Baranzini, S. E., Armañanzas, R., Calvo, B., Muñoz-Culla, M., Khankhanian, P., et al. (2009). Differential micro RNA expression in PBMC from multiple sclerosis patients. PLoS ONE, 4, e6309.

    Article  PubMed Central  PubMed  Google Scholar 

  • Oukka, M. (2007). Interplay between pathogenic Th17 and regulatory T cells. Annals of the Rheumatic Diseases, 66(Suppl. 3), iii87–iii90.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pettinelli, C. B., & McFarlin, D. E. (1981). Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: Requirement for Lyt1 + 2-T lymphocytes. The Journal of Immunology, 127, 1420–1423.

    CAS  PubMed  Google Scholar 

  • Sakaguchi, S. (2005). Naturally arising Foxp3-expressing CD25 + CD4 + regulatory T cells in immunological tolerance to self and non-self. Nature Immunology, 6, 345–352.

    Article  CAS  PubMed  Google Scholar 

  • Sander, S., Bullinger, L., Klapproth, K., Fiedler, K., Kestler, H. A., Barth, T. F., et al. (2008). MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood, 112, 4202–4212.

    Article  CAS  PubMed  Google Scholar 

  • Sospedra, M., & Martin, R. (2005). Immunology of multiple sclerosis. Annual Review of Immunology, 23, 683–747.

    Article  CAS  PubMed  Google Scholar 

  • Tiscornia, G., Singer, O., & Verma, I. M. (2006). Production and purification of lentiviral vectors. Nature Protocols, 1, 241–245.

    Article  CAS  PubMed  Google Scholar 

  • Tzartos, J. S., Friese, M. A., Craner, M. J., Palace, J., Newcombe, J., Esiri, M. M., et al. (2008). Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. The American Journal of Pathology, 172, 146–155.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Windhagen, A., Newcombe, J., Dangond, F., Strand, C., Woodroofe, M. N., Cuzner, M. L., et al. (1995). Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. The Journal of Experimental Medicine, 182, 1985–1996.

    Article  CAS  PubMed  Google Scholar 

  • Xiao, C., & Rajewsky, K. (2009). MicroRNA control in the immune system: Basic principles. Cell, 136, 26–36.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, R., Tian, A., Zhang, H., Zhou, Z., Yu, H., & Chen, L. (2011). Amelioration of experimental autoimmune encephalomyelitis by β-elemene treatment is associated with Th17 and Treg cell balance. Journal of Molecular Neuroscience, 44, 31–40.

    Article  PubMed  Google Scholar 

  • Zhu, S., Pan, W., Song, X., Liu, Y., Shao, X. R., Tang, Y. J., et al. (2012). The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB 2, TAB 3 and IKK-alpha. Nature Medicine, 18, 1077–1086.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The work was supported by grants from the National Natural Science Foundation of China (No. 81100889), the Liaoning Province Scientific Research Foundation for Doctors, China (No. 20111106), and the Liaoning Province Nature Science Foundation, China (No. 2012225021-73).

Conflict of interest

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110001, Liaoning, China

    Rongwei Zhang, Xueli Shen, Guoxian Qi & Yanqing Tang

  2. Department of Anesthesiology, The First Affiliated Hospital of China Medical University, Shenyang, China

    Ayong Tian

  3. Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, China

    Jun Wang

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  1. Rongwei Zhang
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  2. Ayong Tian
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  5. Guoxian Qi
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  6. Yanqing Tang
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Correspondence to Rongwei Zhang.

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Zhang, R., Tian, A., Wang, J. et al. miR26a Modulates Th17/Treg Balance in the EAE Model of Multiple Sclerosis by Targeting IL6. Neuromol Med 17, 24–34 (2015). https://doi.org/10.1007/s12017-014-8335-5

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  • DOI: https://doi.org/10.1007/s12017-014-8335-5

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