Circulating microRNA Expression Profiling Identifies miR-125a-5p Promoting T Helper 1 Cells Response in the Pathogenesis of Hashimoto's Thyroiditis.

Yingzhao Liu,Xiangmei Ding,Li Wang,Shengjun Wang,Huiyong Peng,Xuehua Wang,Si Xiong,Xinyi Tang

doi:10.3389/fimmu.2020.01195

Abstract

MicroRNAs (miRNAs) have emerged as key regulators of cellular processes by suppressing target mRNAs at the posttranscriptional level. However, little is known regarding the expression of miRNAs in peripheral blood mononuclear cells (PBMCs) from Hashimoto's thyroiditis (HT) patients. Therefore, 38 HT patients and 36 healthy volunteers were enrolled in this study to identify HT-mediated changes in miRNA expression. Over 1,000 dysregulated miRNAs and their biological functions in the HT patients were identified. Among them, miR-125a-5p expression was upregulated and inversely correlated with low levels of MAF, a transcription factor that inhibits Th1 cells activity and the production of IFN-γ. Luciferase assay results demonstrated that MAF is a direct target gene of miR-125a-5p. Moreover, the proportion of circulating Th1 cells and the transcript levels of IFN-γ were increased in the HT patients. MiR-125a-5p expression positively correlated with the proportion of circulating Th1 cells and the serum concentrations of anti-thyroperoxidase antibodies in the HT patients. Interestingly, knockdown of miR-125a-5p in CD4+ T cells resulted in an elevated level of MAF but decreased the proportion of Th1 cells and the transcript level of IFN-γ in vitro. Furthermore, upregulated miR-125a-5p and IFN-γ transcript levels and downregulated MAF expression were detected in thyroid tissues from HT patients. Receiver operating characteristic (ROC) curves suggested that miR-125a-5p has a crucial role in the HT. Our results demonstrate that the elevated levels of miR-125a-5p contribute to the Th1 cells response in the HT patients and may be involved in the pathogenesis of HT.

Highlights

Hashimoto’s thyroiditis (HT), known as chronic lymphocytic thyroiditis (CLT), is an organ-specific autoimmune disease that belongs to the spectrum of chronic autoimmune thyroid diseases (AITD) [1]
next-generation high-throughput sequencing (NGS) was performed to identify human miRNAs, and hierarchical clustering analysis results revealed different miRNA expression patterns in peripheral blood mononuclear cells (PBMCs) from the HT and control samples (Figure 1A; red and green squares indicate up- and downregulated miRNAs, respectively)
Using a 1.5-fold change as a cutoff, the results indicated that the levels of miRNAs in the HT samples were distinctly different from those in the control samples

Summary

Introduction

Hashimoto’s thyroiditis (HT), known as chronic lymphocytic thyroiditis (CLT), is an organ-specific autoimmune disease that belongs to the spectrum of chronic autoimmune thyroid diseases (AITD) [1]. HT patients typically exhibit infiltration of lymphocyte cells in the interstitium between thyroid follicles, a diffusely enlarged thyroid gland and elevation of autoantibody production, including anti-thyroglobulin antibody (TgAb) and anti-thyroperoxidase antibody (TPOAb) [2]. Patients can be euthyroid or even clinically manifest thyrotoxicosis, most of them develop hypothyroidism. HT was first described by Hakaru Hashimoto in 1912, and its prevalence exhibits an increasing trend [3]. After more than a century, HT is considered the most common autoimmune disease, endocrine disorder and cause of hypothyroidism [1]. The results of studies suggest that cellular and humoral immune dysregulation are important pathogenic factors in the HT, the underlying pathogenesis remains poorly understood [4]

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