Elevated MicroRNA-326 Levels Regulate the IL-23/IL-23R/Th17 Cell Axis in Hashimoto's Thyroiditis by Targeting a Disintegrin and Metalloprotease 17
Elevated MicroRNA-326 Levels Regulate the IL-23/IL-23R/Th17 Cell Axis in Hashimoto's Thyroiditis by Targeting a Disintegrin and Metalloprotease 17
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microRNA-326 水平升高通过靶向解整合素和金属蛋白酶来调节桥本甲状腺炎中的 IL-23/IL-23R/Th17 细胞轴 17
DOI：
10.1089/thy.2019.0552
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发表时间：
2020-04-24
期刊：
影响因子：
6.6
通讯作者：
Teng, Weiping
中科院分区：
文献类型：
--
作者：
Liu, Yongping;Cui, Xuejiao;Teng, Weiping
背景：microRNAs（miRNAs）是一类重要的表观遗传调节因子，参与多种自身免疫性疾病的发生。我们先前的研究报道了miR-326诱导的桥本甲状腺炎（HT）小鼠模型中T辅助细胞（Th）17细胞的增加，但miR-326在HT患者中的致病作用尚未得到证实。本研究旨在探讨miR-326在HT患者中的致病作用及其分子机制。我们用流式细胞术和实时聚合酶链反应检测了HT患者外周血单个核细胞（PBMC）中Th 17细胞和miR-326是否发生异常改变。采用流式细胞术和Western blot检测细胞膜白细胞介素（IL）-23受体（mIL-23 R）水平，探讨mIL-23 R在Th 17细胞发育中的重要作用。分离的CD 3（+）T细胞用于进一步研究通过去整合素和金属蛋白酶（ADAM 17）的mIL-23 R的胞外域脱落。结果：HT患者外周血单个核细胞中miR-326的表达水平明显高于健康对照组，HT患者外周血单个核细胞中miR-326的表达水平明显高于健康对照组。与IL-23诱导的STAT 3过度活化一致，在极化培养条件下，实质上更多的HT患者来源的PBMC分化为Th 17细胞，这可能至少部分是由增强的mIL-23 R水平引起的。此外，mIL-23 R的胞外结构域脱落酶ADAM 17被miR-326靶向并负调控。结论：miR-326对HT患者IL-23/IL-23 R/Th 17细胞轴的影响可能部分通过靶向ADAM 17实现。
Background: MicroRNAs (miRNAs) are a class of critical epigenetic regulators involved in several autoimmune diseases. Our previous study reported an miR-326-induced increase in T helper (Th) 17 cells in a mouse model of Hashimoto's thyroiditis (HT), but the pathogenic effect of miR-326 in HT patients has not been verified. The goal of the present study was to explore the pathogenic role of miR-326 and its underlying molecular mechanism in HT patients.Methods: A total of 58 HT patients and 55 normal controls were enrolled in this study. We examined whether Th17 cells and miR-326 were aberrantly altered in the peripheral blood mononuclear cells (PBMCs) of HT patients with flow cytometry and real-time polymerase chain reaction. Levels of membrane interleukin (IL)-23R (mIL-23R) were determined by flow cytometry and Western blot to explore the critical role of mIL-23R in the development of Th17 cells. Isolated CD3(+) T cells were used to further investigate the ectodomain shedding of mIL-23R by a disintegrin and metalloprotease (ADAM17). Furthermore, miR-326 inhibitor and mimics were transfected into PBMCs derived from HT patients and healthy controls to verify the regulation of ADAM17 by miR-326.Results: We observed elevated miR-326 levels in the PBMCs of HT patients compared with those in the PBMCs of healthy controls. Consistent with IL-23-induced STAT3 overactivation, substantially more HT patient-derived PBMCs differentiated into Th17 cells under polarization culture conditions, which may, at least in part, have resulted from enhanced mIL-23R levels. Furthermore, ADAM17, an ectodomain sheddase of mIL-23R, was targeted and negatively regulated by miR-326. Inhibiting ADAM17 might attenuate the ectodomain shedding of mIL-23R.Conclusions: Our findings suggest that the effect of miR-326 on the IL-23/IL-23R/Th17 cell axis in HT patients might be partially due to the targeting of ADAM17.