Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
Department of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
Int J Mol Sci. 2020 Nov 14;21(22):8587. doi: 10.3390/ijms21228587.
The aim of this study is to explore the role of microRNAs (miR)-21/23a/146a/150/155 targeting the toll-like receptor pathway in active tuberculosis (TB) disease and latent TB infection (LTBI). Gene expression levels of the five miRs and predicted target genes were assessed in peripheral blood mononuclear cells from 46 patients with active pulmonary TB, 15 subjects with LTBI, and 17 non-infected healthy subjects (NIHS). THP-1 cell lines were transfected with miR-23a-3p mimics under stimuli with Mycobacterium TB-specific antigens. Both miR-155-5p and miR-150-5p gene expressions were decreased in the active TB group versus the NIHS group. Both miR-23a-3p and miR-146a-5p gene expressions were decreased in active TB patients with high bacterial burden versus those with low bacterial burden or control group (LTBI + NIHS). TLR2, TLR4, and interleukin (IL)10 gene expressions were all increased in active TB versus NIHS group. MiR-23a-3p mimic transfection reversed ESAT6-induced reduction of reactive oxygen species generation, and augmented ESAT6-induced late apoptosis and phagocytosis, in association with down-regulations of the predicted target genes, including tumor necrosis factor (TNF)-α, TLR4, TLR2, IL6, IL10, Notch1, IL6R, BCL2, TGF-β1, SP1, and IRF1. In conclusion, the down-regulation of miR-23a-3p in active TB patients with high bacterial burden inhibited mononuclear cell function and phagocytosis through TLR4/TNF-α/TGF-β1/IL-10 signaling via targeting IRF1/SP1.
本研究旨在探讨靶向 Toll 样受体通路的 microRNAs（miR）-21/23a/146a/150/155 在活动性肺结核（TB）病和潜伏性结核感染（LTBI）中的作用。评估了外周血单个核细胞中 5 种 miR 和预测靶基因的表达水平，这些细胞来自 46 例活动性肺结核患者、15 例 LTBI 患者和 17 例非感染健康受试者（NIHS）。在结核分枝杆菌特异性抗原刺激下，将 miR-23a-3p 模拟物转染到 THP-1 细胞系中。miR-155-5p 和 miR-150-5p 的基因表达在活动性 TB 组与 NIHS 组相比均降低。在高细菌负荷的活动性 TB 患者中，miR-23a-3p 和 miR-146a-5p 的基因表达均低于低细菌负荷或对照组（LTBI+NIHS）。与 NIHS 组相比，TLR2、TLR4 和白细胞介素（IL）10 的基因表达在活动性 TB 组中均增加。miR-23a-3p 模拟物转染逆转了 ESAT6 诱导的活性氧生成减少，并增强了 ESAT6 诱导的晚期凋亡和吞噬作用，与预测靶基因的下调有关，包括肿瘤坏死因子（TNF）-α、TLR4、TLR2、IL6、IL10、Notch1、IL6R、BCL2、TGF-β1、SP1 和 IRF1。总之，高细菌负荷的活动性 TB 患者中 miR-23a-3p 的下调通过靶向 IRF1/SP1 抑制单核细胞功能和吞噬作用，通过 TLR4/TNF-α/TGF-β1/IL-10 信号通路。
