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Identification of Novel MicroRNA Signatures Linked to Experimental Autoimmune Myasthenia Gravis Pathogenesis: Down-Regulated miR-145 Promotes Pathogenetic Th17 Cell Response

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Abstract

Emerging evidence demonstrates that miRNAs, a new family of key mRNA regulatory molecules, have crucial roles in controlling and modulating immunity. Their contribution to myasthenia gravis (MG), a T cell-dependent, antibody-mediated nervous system autoimmune disease, has not been thoroughly investigated. In the present study, using a highly sensitive microarray-based approach, we identified 11 miRNAs with differential expression between Peripheral Blood Mononuclear Cells (PBMC) from experimental autoimmune MG (EAMG) rats and control rats. miR-145 is one of the most significantly down-regulated miRNAs in PBMC from EAMG rats. Down-regulation of miR-145 expression was confirmed in PBMC and CD4+CD25- T cells (T effector cells) from both EAMG rats and MG patients by real-time PCR. Bioinformatics target prediction identified two crucial immune-related molecules-CD28 and NFATc1, as putative targets of miR-145. Furthermore, miR-145 inhibited CD28 and NFATc1 expression by directly targeting their 3′-UTRs, which was abolished by mutation of the miR-145 and CD28/NFATc1 binding sites. In vitro up-regulation of miR-145 in CD4+ T cells can significantly reduce CD28 protein levels accompanied by decreased proliferative response. In a dendritic cell (DC)-T cell coculture system, overexpression of miR-145 in AChR-specific CD4+ T cells suppresses NFATc1 expression and T Helper 17 cells level. Finally, we observed that administration of lentiviral-miR-145 decreased the severity of ongoing, established EAMG with decreased IL-17 production, and also decreased serum anti-AChR IgG levels. Our studies provide an important new insight into the pathogenesis of EAMG and MG, which may open a new perspective for the development of effective gene therapy for EAMG/MG.

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Acknowledgments

This work was supported by National Nature Science Foundation of China (81072465), Natural Science Fund of the Educational Committee of Jiangsu Province (10KJD320003), Special foundation of president of the Xuzhou Medical College (2010KJZ01), Key medical talents fund of Jiangsu Province (H201130), Jiangsu Province ordinary university postgraduate research innovation fund (CXLX11_0734, CXLX13_992).

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The authors have no financial conflict of interest.

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Authors and Affiliations

  1. Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, 99 West Huai-hai Rd, Xuzhou, China, 221002

    Jiao Wang, Shuangshuang Zheng, Ning Xin, Changxin Dou, Xiuying Zhang, Jing Chen, Yanyan Zhang, Deqin Geng, Chenghua Xiao, Guiyun Cui, Xia Shen, Yang Lu, Jinhua Wang, Ruiguo Dong & Yong Zhang

  2. Department of Rehabilitation Medicine, Lishui People’s Hospital, Lishui, Zhejiang Province, China

    Shuangshuang Zheng

  3. Department of Pathogenic Biology and Laboratory of Infection and Immunology, Xuzhou Medical College, Xuzhou, Jiangsu, China

    Linlin Fu

  4. Department of Otolaryngology, The Affiliated Hospital of Xuzhou Medical College, 99 West Huai-hai Rd, Xuzhou, China, 221002

    Yuehua Qiao

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  1. Jiao Wang
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  14. Jinhua Wang
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Correspondence to Ruiguo Dong or Yong Zhang.

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Jiao Wang and Shuangshuang Zheng contributed equally to this work.

Ruiguo Dong is a co-corresponding author. Yong Zhang: to whom correspondence should be addressed.

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Wang, J., Zheng, S., Xin, N. et al. Identification of Novel MicroRNA Signatures Linked to Experimental Autoimmune Myasthenia Gravis Pathogenesis: Down-Regulated miR-145 Promotes Pathogenetic Th17 Cell Response. J Neuroimmune Pharmacol 8, 1287–1302 (2013). https://doi.org/10.1007/s11481-013-9498-9

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