Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
Front Immunol. 2021 Jan 14;11:580838. doi: 10.3389/fimmu.2020.580838. eCollection 2020.
Accumulated evidence has demonstrated that the macrophage phenotypic switch from M0 to M1 is crucial in the initiation of the inflammatory process of acute respiratory distress syndrome (ARDS). Better insight into the molecular control of M1 macrophages in ARDS may identify potential therapeutic targets. In the current study, 36 candidate genes associated with the severity of ARDS and simultaneously involved in M1-polarized macrophages were first screened through a weighted network algorithm on all gene expression profiles from the 26 ARDS patients and empirical Bayes analysis on the gene expression profiles of macrophages. , and were subsequently identified as hub genes according to connectivity degree analysis and multiple external validations. Among these candidate genes, had the strongest connection with ARDS through the RobustRankAggreg algorithm. It was selected as a crucial gene for further investigation. validation, the RAW264.7 cell line and BMDMs were transfected with sh lentivirus and plasmid expression vectors of . Cellular experimental studies further confirmed that was a novel regulator for promoting M1 macrophage polarization. Moreover, gene set enrichment analysis (GSEA) and validations indicated that regulated M1 polarization by activating . In addition, previous studies demonstrated that activation of was stimulated by viral RNAs or RNA mimics. Surprisingly, the current study found that LPS could also induce - activation MyD88-dependent mechanism. We also found that only expression without LPS or RNA mimic stimulation could not affect activation and M1 macrophage polarization. These findings were validated on two types of macrophages, RAW264.7 cells and BMDMs, which expanded the knowledge on the inflammatory roles of and , suggesting as a potential target for ARDS treatment.
已有大量证据表明，巨噬细胞从 M0 表型向 M1 表型的转换在急性呼吸窘迫综合征 (ARDS) 的炎症过程起始中起关键作用。更好地了解 ARDS 中 M1 巨噬细胞的分子调控可能确定潜在的治疗靶点。在本研究中，首先通过加权网络算法对 26 名 ARDS 患者的所有基因表达谱和巨噬细胞基因表达谱的经验贝叶斯分析，筛选出与 ARDS 严重程度相关且同时参与 M1 极化巨噬细胞的 36 个候选基因。根据连通度分析和多重外部验证，随后鉴定 、 和 为枢纽基因。在这些候选基因中，通过 RobustRankAggreg 算法与 ARDS 具有最强连接的 。它被选为进一步研究的关键基因。通过 sh 慢病毒和 的质粒表达载体转染 RAW264.7 细胞系和 BMDMs 进行 验证，细胞实验研究进一步证实 是促进 M1 巨噬细胞极化的新调节因子。此外，基因集富集分析 (GSEA) 和 验证表明 通过激活 来调节 M1 极化。此外，先前的研究表明 激活是由病毒 RNA 或 RNA 模拟物刺激引起的。令人惊讶的是，本研究发现 LPS 也可以通过 MyD88 依赖性机制诱导 - 激活。我们还发现，没有 LPS 或 RNA 模拟物刺激的仅 表达不会影响 激活和 M1 巨噬细胞极化。这些发现在两种类型的巨噬细胞（RAW264.7 细胞和 BMDMs）上得到了验证，扩展了 和 在炎症中的作用的知识，表明 是 ARDS 治疗的潜在靶点。
