Department of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.
The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.
Front Immunol. 2022 May 25;13:897487. doi: 10.3389/fimmu.2022.897487. eCollection 2022.
N6-methyladenosine (mA) RNA modification is a fundamental determinant of mRNA metabolism in eukaryotic cells and is involved in numerous physiological and pathological processes. However, the specific role of mA modification in sepsis-induced acute respiratory distress syndrome(ARDS) remains unknown. Here, we show that the levels of mA RNA were significantly decreased in septic lungs and that METTL3 was the main regulator involved in the absence of mA RNA modification. Pulmonary endothelial barrier damage is a critical process in the pathogenesis of acute lung injury during sepsis. METTL3 regulated endothelial barrier dysfunction and inflammatory responses in sepsis-induced ARDS and . Furthermore, we identified tripartite motif-containing (Trim)59 as a key mA effector and Trim59 deficiency exacerbated lung injury. Mechanistically, METTL3 inhibited endothelial injury in sepsis-induced ARDS through Trim59-associated NF-κB inactivation. Our findings revealed novel insights into epitranscriptional mechanisms in sepsis-induced ARDS mA modifications, which has important application value in the diagnosis, prognosis, and molecular-targeted therapy of sepsis-associated lung injury.
N6-甲基腺苷(m6A)RNA 修饰是真核细胞 mRNA 代谢的基本决定因素，参与多种生理和病理过程。然而，m6A 修饰在脓毒症诱导的急性呼吸窘迫综合征(ARDS)中的具体作用尚不清楚。在这里，我们发现 m6A RNA 的水平在脓毒症肺中显著降低，并且 METTL3 是参与缺乏 m6A RNA 修饰的主要调节剂。肺血管内皮屏障损伤是脓毒症期间急性肺损伤发病机制中的一个关键过程。METTL3 调节脓毒症诱导的 ARDS 中的内皮屏障功能障碍和炎症反应。此外，我们鉴定了三基序蛋白 59(Trim59)作为关键的 m6A 效应物，Trim59 缺乏加剧了肺损伤。在机制上，METTL3 通过与 Trim59 相关的 NF-κB 失活抑制了脓毒症诱导的 ARDS 中的内皮损伤。我们的研究结果揭示了脓毒症诱导的 ARDS 中转录后修饰的新见解，这在与脓毒症相关的肺损伤的诊断、预后和分子靶向治疗中具有重要的应用价值。
