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MicroRNA-125b regulates Th17/Treg cell differentiation and is associated with juvenile idiopathic arthritis

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Abstract

Background

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood driven by aberrant pathways of T-cell activation. T helper 17 (Th17)/regulatory T cell (Treg) imbalance plays critical roles in the pathogenesis of arthritis. MicroRNA-125b (miR-125b) was upregulated after the activation of the initial CD4+ T cells, and could regulate the differentiation of CD4+ T cells. However, the effects of miR-125b on Th17/Treg imbalance and differentiation of Th17/Treg cells remain unknown.

Methods

In this study, we evaluated the expression of miR-125b in the peripheral blood mononuclear cells (PBMCs) of children with JIA, and the relationship of miR-125b with Th17/Treg imbalance. Then, we used lentivirus vector-mediated overexpression technology to investigate the regulatory function of miR-125b in CD4+ T cells or dendritic cell/CD4+ T co-culture system.

Results

Decreased miR-125b expression in PBMCs and CD4+ T cells of JIA patients was negatively correlated with the ratio of Th17/Treg cells. It also correlated negatively with retinoic acid receptor-related orphan receptor γt but positively with Forkhead box protein 3 at transcriptional levels. Furthermore, we found that miR-125b overexpression inhibited Th17 cell differentiation, whereas facilitated the differentiation of Treg cells. MiR-125b upregulation led to the decrease of Th17-secreting cytokines but the increase of the Treg-secreting cytokines.

Conclusions

Our results demonstrate that miR-125b participated in regulating Th17/Treg cell differentiation and imbalance in JIA patients. These findings provide novel insight into the critical role of miR-125b in the Th17/Treg imbalance of JIA, and raise the distinct possibility that miR-125b may prove to be a potential therapeutic target for JIA.

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Acknowledgements

We are grateful to Lei Zhang from Nanjing Medical University for his support on this project.

Funding

This study was supported by National Natural Science Foundation of China (Nos. 81202345, 81771762, 81170661 and 31640048), Nanjing Science and Technology Development Program (No. 201503003) and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Zhi-Dan Fan, Qian Cao & Guo-Ping Zhou

  2. Department of Rheumatology and Immunology, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, China

    Zhi-Dan Fan, Na Huang, Le Ma, Hui-Hui Ma, Ya-Yuan Zhang & Hai-Guo Yu

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  1. Zhi-Dan Fan
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Contributions

ZDF and GPZ equally contributed to the conception and design of the research, and drafted the manuscript. QC, NH and LM contributed to the acquisition and analysis of the data; HHM and YYZ contributed to the interpretation of the data. HGY contributed to the design of the research. HGY and GPZ contributed equally to this work. All authors critically revised the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.

Corresponding author

Correspondence to Guo-Ping Zhou.

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Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. A statement to confirm all methods was carried out in accordance with relevant guidelines and regulations. A statement to confirm that all experimental protocols were approved by the Ethics Committee of the Hospital, and all patients signed the informed consent.

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Fan, ZD., Cao, Q., Huang, N. et al. MicroRNA-125b regulates Th17/Treg cell differentiation and is associated with juvenile idiopathic arthritis. World J Pediatr 16, 99–110 (2020). https://doi.org/10.1007/s12519-019-00265-z

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