Research Paper Volume 11, Issue 13 pp 4463—4477

Let-7f-5p suppresses Th17 differentiation via targeting STAT3 in multiple sclerosis

Zhi-Hui Li 1, , Yi-Fei Wang 1, , Dan-Dan He 2, , Xue-Mei Zhang 1, , Ying-Lian Zhou 1, , Hui Yue 1, , Shan Huang 1, , Zheng Fu 3, , Ling-Yu Zhang 1, , Zhu-Qing Mao 1, , Shuang Li 1, , Chen-Yu Zhang 3, , Xi Chen 3, , Jin Fu 1, ,

  • 1 Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang 150086, China
  • 2 Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin Heilongjiang 150086, China
  • 3 Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093,China

received: March 21, 2019 ; accepted: July 10, 2019 ; published: July 15, 2019 ;

https://doi.org/10.18632/aging.102093
How to Cite

Copyright: Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

T helper 17 (Th17) cells are regarded as key factors in the pathogenesis of multiple sclerosis (MS). Although the involvement of certain microRNAs (miRNAs) in the development of MS has been reported, their roles in Th17 cell differentiation and MS pathogenesis remain elusive. In this study, we identified that let-7f-5p expression is significantly downregulated in CD4+ T cells from MS patients and during the process of Th17 differentiation. The overexpression of let-7f-5p suppressed Th17 differentiation, whereas the knockdown of let-7f-5p expression enhanced this progress. We then explored the molecular mechanism through which let-7f-5p suppressed Th17 differentiation and identified signal transducer and activator of transcription 3 (STAT3), a pivotal transcription factor of Th17 cells, as a direct target of let-7f-5p. In contrast to the downregulated expression of let-7f-5p, STAT3 and p-STAT3 protein levels were dramatically upregulated and inversely correlated with let-7f-5p in peripheral blood CD4+ T cells from MS patients. In conclusion, let-7f-5p functions as a potential inhibitor of Th17 differentiation in the pathogenesis of MS by targeting STAT3 and may serve as a new therapeutic target.

Abbreviations

MS: multiple sclerosis; HC: healthy controls; CNS: central nervous system; Th: T helper; EAE: experimental autoimmune encephalomyelitis; PORC: RAR related orphan receptor C; RORγt: retinoic acid receptor-related orphan receptor-γt; STAT3: signal transducer and activator of transcription 3; CSF: cerebrospinal fluid; 3’-UTRs: 3’ untranslated regions; RT-PCR: real-time PCR; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; OGT: O-GlcNAc transferase; JAK-2: Janus kinase 2; MRI: magnetic resonance imaging; EDSS: Expanded Disability Status Scale; RRMS: relapsing-remitting multiple sclerosis; PBMCs: peripheral blood mononuclear cells; FCM: flow cytometry; HEK: human embryonic kidney; FBS: fetal bovine serum; PS: penicillin/streptomycin; AMV: avian myeloblastosis virus; ELISA: enzyme-linked immunosorbent assay.