Department of Pediatrics, Ren Min Hospital of Wuhan University, WuHan, People's Republic of China.
PLoS One. 2019 Feb 26;14(2):e0212063. doi: 10.1371/journal.pone.0212063. eCollection 2019.
MicroRNAs (miRNAs) are small non-coding RNA molecules that play an important role in the regulation of gene expression related to inflammatory responses. Human adipose stem cells are characterized by pluripotent differentiation potential and isolated from adipose tissues. These cells regulate inflammation mainly by interacting with immune cells and affecting the secretion of immune factors; details of this interaction are currently unknown. In the current study, we successfully established an acute inflammation model and a chronic inflammation model involving adipose stem cells. We used high-throughput miRNA microarray analysis to identify miRNAs that were significantly (p < 0.05) differentially expressed during both acute and chronic inflammation. Lipopolysaccharide (LPS) significantly (p < 0.05) reduced the expression of miR-223-3P and miR-2909, while promoting the production of pro-inflammatory cytokines, interleukin (IL) 6, IL-1β, and tumor necrosis factor (TNF)-α via the Toll-like receptor (TLR) 4/TLR2/nuclear factor (NF)-κB/signal transducer and activator of transcription (STAT) 3 signaling pathway in human adipose stem cells. Further, miR-223-3P expression was significantly (p < 0.05) reduced in human adipose stem cells during activation by IL-6 stimulation. The inducible down-regulation of miR-223-3P resulted in the activation of STAT3, which was directly targeted by miR-223-3P. STAT3 directly targeted TLR4 and TLR2, promoting the production of the pro-inflammatory cytokine, IL-6, and formed a positive feedback loop to regulate IL-6 levels. Similarly, TNF-α significantly (p < 0.05) increased the expression of miR-223-3p, with LPS and TLR4/TLR2/NF-κB/STAT3 forming a negative feedback loop to regulate TNF-α levels. In addition, miR-2909, which depends on NF-κB, targeted Krueppel-like factor (KLF) 4 to regulate the levels of pro-inflammatory cytokines, IL-6, IL-1β, and TNF-α. We conclude that miR-223-3p and miR-2909 form a complex regulatory network with pro-inflammatory factors and signaling pathways in adipose stem cells stimulated by LPS. These findings will inform the development of therapies against autoimmune and inflammatory diseases.
微小 RNA（miRNA）是一种小的非编码 RNA 分子，在与炎症反应相关的基因表达调控中发挥着重要作用。人脂肪干细胞的特征是多能分化潜能，并从脂肪组织中分离出来。这些细胞主要通过与免疫细胞相互作用和影响免疫因子的分泌来调节炎症；目前尚不清楚这种相互作用的细节。在目前的研究中，我们成功建立了涉及脂肪干细胞的急性炎症模型和慢性炎症模型。我们使用高通量 miRNA 微阵列分析来鉴定在急性和慢性炎症期间显著（p<0.05）差异表达的 miRNA。脂多糖（LPS）通过 Toll 样受体（TLR）4/TLR2/核因子（NF）-κB/信号转导和转录激活因子（STAT）3 信号通路显著（p<0.05）降低 miR-223-3P 和 miR-2909 的表达，同时促进促炎细胞因子白细胞介素（IL）6、IL-1β 和肿瘤坏死因子（TNF）-α的产生，在人脂肪干细胞中。此外，IL-6 刺激激活人脂肪干细胞时，miR-223-3P 的表达显著（p<0.05）降低。miR-223-3P 的诱导下调导致 STAT3 的激活，而 STAT3 直接靶向 miR-223-3P。STAT3 直接靶向 TLR4 和 TLR2，促进促炎细胞因子 IL-6 的产生，并形成正反馈环以调节 IL-6 水平。同样，TNF-α显著（p<0.05）增加 miR-223-3p 的表达，LPS 和 TLR4/TLR2/NF-κB/STAT3 形成负反馈环以调节 TNF-α 水平。此外，依赖 NF-κB 的 miR-2909 靶向 Krueppel 样因子（KLF）4 以调节促炎细胞因子 IL-6、IL-1β 和 TNF-α的水平。我们得出结论，miR-223-3p 和 miR-2909 与 LPS 刺激的脂肪干细胞中的促炎因子和信号通路形成了一个复杂的调控网络。这些发现将为针对自身免疫和炎症性疾病的治疗方法的开发提供信息。
