Cell Death Dis|邢丽华团队指出TUG1/miR-9-5p/SIRT1在败血症巨噬细胞极化中的作用机制

2022年8月4日 0条评论 299次阅读 0人点赞

最新细胞功能及机制文献分享

来自内皮祖细胞（EPC）的细胞外囊泡（EVs）递送的生物分子已被证明可改善败血症，但其治疗机制仍有待阐明。EVs一词包括外泌体、微囊泡和其他囊泡，其可运输脂质、肽、RNA和糖类等物质，这些物质对于炎症条件下的各种细胞过程至关重要。2021年11月6日，郑州大学第一附属医院呼吸重症监护科邢丽华团队在Cell Death and Disease上发表了题为“Functional delivery of lncRNA TUG1 by endothelial progenitor cells derived extracellular vesicles confers anti-inflammatory macrophage polarization in sepsis via impairing miR-9-5p-targeted SIRT1 inhibition”的研究论文。在本研究中，团队旨在盲肠结扎和穿刺（CLP）诱导的败血症小鼠模型中探讨源自EPC的EVs的TUG1对巨噬细胞极化以及巨噬细胞介导的炎症的影响。

败血症是一种由微生物感染引发的功能失调性全身炎症疾病，经常导致器官衰竭和死亡，最近的研究证明EVs可作为新型诊断分子或预防败血症的关键载体，其可用于开发个性化治疗。研究显示，源自EPC的EVs增强了败血症微血管功能障碍的保护作用，其中，lncRNA TUG1已被确定为与败血症最相关的五种lncRNAs之一。一些研究人员已证明，在败血症中TUG1下调，确定了其作为败血症诱导炎症和急性肾损伤抑制剂的潜力。最近的一项研究提出，ceRNA调节网络可用于研究败血症病理生理学的潜在机制，有趣的是，TUG1和的ceRNA网络已被确定参与人类骨肉瘤的进展，并且Starbase网站预测显示，SIRT1是miR-9-5p的下游靶标。SIRT1是NAD⁽⁺⁾依赖性III类的蛋白质脱乙酰酶，被认为是关键的免疫介质，不仅可调控各种促炎因子的表达，还可影响巨噬细胞极化。

基于上述事实，团队通过对雄性C57BL/6小鼠模型以及小鼠巨噬细胞系RAW264.7体外实验数据的分析发现，TUG1在CLP诱导的败血症中低表达，其过表达可诱导抗炎巨噬细胞（M2型）极化并抑制巨噬细胞对肺血管内皮的炎症损伤。接下来的荧光素酶报告实验、RIP和RNA下拉实验数据分析表明，TUG1可竞争性结合miR-9-5p上调SIRT1的表达，从而调控巨噬细胞极化。最后，团队还证实携带TUG1的EPC衍生EVs可改善小鼠模型中败血症引起的器官损伤。

总而言之，此项研究通过在败血症体内外模型中阻断miR-9-5p诱导的SIRT1沉默，为TUG1对巨噬细胞极化及其抗炎效力的贡献提供了证据，为靶向EPC来源的EVs分泌的TUG1用于临床治疗败血症提供了一种潜在策略。

《Cell Death Dis|邢丽华团队指出TUG1/miR-9-5p/SIRT1在败血症巨噬细胞极化中的作用机制》

图 TUG1/miR-9-5p/SIRT1信号通路在败血症巨噬细胞极化调节中的功能作用示意图。TUG1在脓毒症中下调，其可削弱miR-9-5p对SIRT1的靶向抑制，有助于改善败血症引起的炎症损伤。

期刊及DOI号

Cell Death Dis. 2021 Nov 6.

doi: 10.1038/s41419-021-04117-5.

题目

Functional delivery of lncRNA TUG1 by endothelial progenitor cells derived extracellular vesicles confers anti-inflammatory macrophage polarization in sepsis via impairing miR-9-5p-targeted SIRT1 inhibition

摘要

The delivery of biomolecules by extracellular vesicles (EVs) derived from endothelial progenitor cells (EPCs) has been proven to ameliorate sepsis, yet the therapeutic mechanism remains to be elucidated. Taurine upregulated gene 1 (TUG1) is a long noncoding RNA (lncRNA) that is downregulated in sepsis. The current study was designed to explore the role of EPCs derived EVs transmitting TUG1 in macrophage polarization and macrophage-mediated inflammation in a cecal ligation and puncture (CLP)-induced sepsis mouse model. TUG1 was underexpressed in CLP-induced sepsis, and its reexpression induced anti-inflammatory macrophage polarization and suppressed macrophage-medicated inflammatory injury to the pulmonary vascular endothelium. EPCs derived EVs transmitted TUG1 to promote M2 macrophage polarization. Luciferase, RIP, and RNA pull-down assays showed that TUG1 could competitively bind to microRNA-9-5p (miR-9-5p) to upregulate the expression of sirtuin 1 (SIRT1). Furthermore, EPCs derived EVs transmitted TUG1 to promote M2 macrophage polarization through the impairment of miR-9-5p-dependent SIRT1 inhibition. Finally, EPCs derived EVs carrying TUG1 were verified to ameliorate sepsis-induced organ damage in the murine model. In summary, EPCs derived EVs transmit TUG1 to attenuate sepsis via macrophage M2 polarization. This study also highlights the proinflammatory mechanism associated with miR-9-5p-mediated inhibition of SIRT1, which contributes to a more comprehensive understanding of the pathogenesis of sepsis.