MicroRNA-125b regulates Th17/Treg cell differentiation and is associated with juvenile idiopathic arthritis
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.
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.
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.
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.
KeywordsCD4+ T-cell differentiation Juvenile idiopathic arthritis MicroRNA-125b Th17 cells Treg cells
We are grateful to Lei Zhang from Nanjing Medical University for his support on this project.
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.
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.
Compliance with ethical standards
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.
Conflict of interest
No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.
- 4.Cope AP, Schulze-Koops H, Aringer M. The central role of T cells in rheumatoid arthritis. Clin Exp Rheumatol. 2007;25(5 Suppl 46):S4–11.Google Scholar
- 16.Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390–2.Google Scholar
- 17.Vittecoq O, Pouplin S, Krzanowska K, Jouen-Beades F, Menard JF, Gayet A, et al. Rheumatoid factor is the strongest predictor of radiological progression of rheumatoid arthritis in a 3-year prospective study in community-recruited patients. Rheumatology (Oxford). 2003;42:939–46.CrossRefGoogle Scholar
- 34.Lubberts E, Koenders MI, Oppers-Walgreen B, van den Bersselaar L, Coenen-de Roo CJ, Joosten LA, et al. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum. 2004;50:650–9.CrossRefGoogle Scholar
- 37.Yang Y, Wang JK. The functional analysis of MicroRNAs involved in NF-κB signaling. Eur Rev Med Pharmacol Sci. 2016;20:1764–74.Google Scholar