Lincenc1 regulates the lipopolysaccharide-induced inflammatory response in macrophages

摘要/摘要 革兰氏阴性(G-)细菌经常在宿主体内诱导压倒性的炎症反应。尽管多年来 研究表明，G-细菌感染后炎症反应的调节尚不清楚，因此 阻碍新的治疗/诊断策略的发展。哺乳动物基因组编码数千 长非编码RNA(LncRNAs)。LncRNAs在多种免疫细胞中广泛表达，包括 单核细胞和巨噬细胞。据报道，lncRNAs参与了多种生物过程， 包括基因表达的调节、剂量补偿和基因组印迹，但作为 然而，关于它们如何在寄主过程中改变细胞分化/功能的研究很少。 病原体相互作用。我们发现Lincenc1在小鼠的肺中被显著地诱导 被G-细菌感染或接触内毒素后，G-杆菌外膜的一种丰富的糖脂 细菌。此外，我们的体外数据表明，Lincenc1在巨噬细胞中被诱导，而在其他细胞中不被诱导。 如上皮细胞和中性粒细胞。在功能上，Lincenc1促进经典的激活 巨噬细胞和炎性细胞因子的分泌。在这里，我们提出lncRNA Lincenc1促进 G-细菌/脂多糖通过激活肺泡巨噬细胞诱导肺部炎症。为了检验这一假设，我们 提出以下两个特定目标：特定目标I：研究Lincenc1在巨噬细胞中的作用 体外激活。特异性目的2：探讨Lincenc1在体内肺部炎症中的作用。成功 完成拟议的目标将揭示Lincenc1在G-细菌感染中的作用。本研究 这可能有助于确定肺部炎症和损伤的新机制和/或治疗策略。

Summary/Abstract Gram-negative (G-) bacteria frequently induce an overwhelming inflammatory response in hosts. Despite years of research, the regulation of the inflammatory response after G- bacterial infection remains unclear, thus impeding the development of novel therapeutic/diagnostic strategies. Mammalian genomes encode thousands of long non-coding RNAs (lncRNAs). LncRNAs are extensively expressed in various immune cells including the monocytes, and macrophages. The lncRNAs have been reported to be involved in diverse biological processes, including the regulation of the expression of genes, the dosage compensation and genomics imprinting, but as yet very less research has been carried out to explore how they alter cell differentiation/function during host- pathogens interactions. We found that Lincenc1 is strikingly induced in the lungs obtained from the mice infected with G- bacteria or after exposure to LPS, an abundant glycolipid of the outer membrane of G- bacteria. Furthermore, our in vitro data suggest that Lincenc1 is induced in macrophages but not in other cells, such as the epithelial cells and neutrophils. Functionally, Lincenc1 promotes the classical activation of macrophages and the secretion of inflammatory cytokines. Here we propose that lncRNA Lincenc1 promotes G- bacterial/LPS induced lung inflammation via activating alveolar macrophages. To test this hypothesis, we propose the following two specific aims: Specific Aim I: To investigate the role of Lincenc1 in macrophage activation in vitro. Specific Aim 2: To investigate the role of Lincenc1 in lung inflammation in vivo. Successful completion of the proposed aims will uncover the role of Lincenc1 in G- bacterial infections. This study potentially will help to identify novel mechanisms and/or therapeutic strategies for lung inflammation and injury.