Molecular and cellular pathology of Alcohol Laboratory, Prince Felipe Research Center, Valencia, Spain.
Bioinformatics & Biostatistics Unit, Prince Felipe Research Center, Valencia, Spain.
PLoS One. 2020 Aug 11;15(8):e0237066. doi: 10.1371/journal.pone.0237066. eCollection 2020.
TLR4 is a member of the toll-like receptors (TLR) immune family, which are activated by lipopolysaccharide, ethanol or damaged tissue, among others, by triggering proinflammatory cytokines release and inflammation. Lack of TLR4 protects against inflammatory processes and neuroinflammation linked with several neuropathologies. By considering that miRNAs are key post-transcriptional regulators of the proteins involved in distinct cellular processes, including inflammation, this study aimed to assess the impact of the miRNAs profile in mice cortices lacking the TLR4 response. Using mice cerebral cortices and next-generation sequencing (NGS), the findings showed that lack of TLR4 significantly reduced the quantity and diversity of the miRNAs expressed in WT mice cortices. The results also revealed a significant down-regulation of the miR-200 family, while cluster miR-99b/let-7e/miR-125a was up-regulated in TLR4-KO vs. WT. The bioinformatics and functional analyses demonstrated that TLR4-KO presented the systematic depletion of many pathways closely related to the immune system response, such as cytokine and interleukin signaling, MAPK and ion Channels routes, MyD88 pathways, NF-κβ and TLR7/8 pathways. Our results provide new insights into the molecular and biological processes associated with the protective effects of TLR-KO against inflammatory damage and neuroinflammation, and reveal the relevance of the TLR4 receptors response in many neuropathologies.
TLR4 是 toll 样受体 (TLR) 免疫家族的成员，该家族可被脂多糖、乙醇或受损组织等激活，通过触发促炎细胞因子的释放和炎症反应。TLR4 的缺失可防止与多种神经病理学相关的炎症过程和神经炎症。鉴于 miRNA 是参与不同细胞过程（包括炎症）的蛋白质的关键转录后调控因子，本研究旨在评估 TLR4 缺失小鼠皮质中 miRNA 谱的影响。使用小鼠大脑皮质和下一代测序 (NGS)，研究结果表明，TLR4 的缺失显著降低了 WT 小鼠皮质中表达的 miRNA 的数量和多样性。结果还显示 miR-200 家族的显著下调，而 miR-99b/let-7e/miR-125a 簇在 TLR4-KO 与 WT 相比上调。生物信息学和功能分析表明，TLR4-KO 存在与免疫系统反应密切相关的许多途径的系统性耗竭，如细胞因子和白细胞介素信号、MAPK 和离子通道途径、MyD88 途径、NF-κβ 和 TLR7/8 途径。我们的研究结果为 TLR-KO 对炎症损伤和神经炎症的保护作用相关的分子和生物学过程提供了新的见解，并揭示了 TLR4 受体反应在许多神经病理学中的相关性。
