LncRNA GAS5 suppresses inflammatory responses by inhibiting HMGB1 release via miR-155-5p/SIRT1 axis in sepsis
LncRNA GAS5 suppresses inflammatory responses by inhibiting HMGB1 release via miR-155-5p/SIRT1 axis in sepsis
复制标题
脓毒症中 LncRNA GAS5 通过 miR-155-5p/SIRT1 轴抑制 HMGB1 释放来抑制炎症反应
DOI：
10.1016/j.ejphar.2023.175520
复制
发表时间：
2023-01-24
影响因子：
5
通讯作者：
Yuan，Zhiqiang
中科院分区：
文献类型：
--
作者：
Zeng，Zhuo;Lan，Yingying;Yuan，Zhiqiang
脓毒症包括由于感染引起的致命免疫反应。越来越多的证据表明长链非编码 RNA 生长停滞特异性转录物 5 (GAS5) 在脓毒症调节中的重要作用。然而，GAS5 参与脓毒症进展的机制仍不清楚。我们的研究证明了 GAS5 在调节脂多糖 (LPS) 诱导的炎症中的作用和潜在机制。本研究发现脓毒症患者和脓毒症小鼠模型血清样本中GAS5表达量显着降低，且与HMGB1表达量呈负相关。 GAS5 过表达通过减少 HMGB1 释放来抑制细胞炎症反应。此外，GAS5 通过增加 Sirtuin1 (SIRT1) 的表达来抑制 LPS 介导的过度乙酰化和 HMGB1 的释放。此外，GAS5 上调可减弱体外和体内炎症反应，而 miR-155-5p 模拟物和 SIRT1 的敲除可挽救 GAS5 上调的影响。从机制上讲，GAS5 海绵 miR-155-5p 上调 SIRT1，从而抑制 HMGB1 乙酰化和释放。总之，我们的研究结果表明，GAS5 通过调节脓毒症中的 miR-155-5p/SIRT1/HMGB1 轴来抑制炎症反应，为脓毒症炎症提供了新的治疗靶点。
Sepsis comprises a lethal immunologic response due to infection. Increasingly, evidence has demonstrated the important role of long non-coding RNA growth arrest-specific transcript 5 (GAS5) in the regulation of sepsis. Nevertheless, the mechanisms by which GAS5 participates in the progression of sepsis remain unclear. Our study demonstrated the role and underlying mechanism of GAS5 in regulating lipopolysaccharide (LPS)-induced inflammation. In this study, GAS5 expression was found to be markedly decreased in serum samples of sepsis patients and a sepsis mouse model, and was negatively related with HMGB1 expression. GAS5 overexpression inhibited cell inflammatory responses by decreasing HMGB1 release. Furthermore, GAS5 inhibited LPS-mediated hyperacetylation and the release of HMGB1 by increasing the expression of sirtuin1 (SIRT1). Additionally, upregulated GAS5 attenuated inflammatory responsesin vitroandvivo, and the knockdown of a miR-155-5p mimic and SIRT1 rescued the effects of GAS5 upregulation. Mechanistically, GAS5 sponged miR-155-5p to upregulate SIRT1, thereby inhibiting HMGB1 acetylation and release. In conclusion, our findings indicate that GAS5 suppresses inflammatory responses by modulating the miR-155-5p/SIRT1/HMGB1 axis in sepsis, providing a novel therapeutic target for inflammation in sepsis.