Department of Anesthesiology (Hei Long Jiang Province Key Lab of Research on Anesthesiology and Critical Care Medicine).
Department of Periodontology and Oral Mucosa, The Second Affiliated Hospital, Harbin Medical University.
Int J Surg. 2024 May 1;110(5):2649-2668. doi: 10.1097/JS9.0000000000001215.
Acute lung injury (ALI) is a leading cause of mortality in patients with sepsis due to proinflammatory endothelial changes and endothelial permeability defects. Mitochondrial dysfunction is recognized as a critical mediator in the pathogenesis of sepsis-induced ALI. Although mitophagy regulation of mitochondrial quality is well recognized, little is known about its role in lung ECs during sepsis-induced ALI. Sirtuin 1 (SIRT1) is a histone protein deacetylase involved in inflammation, mitophagy, and cellular senescence. Here, the authors show a type of late endosome-dependent mitophagy that inhibits NLRP3 and STING activation through SIRT1 signaling during sepsis-induced ALI.
C57BL/6J male mice with or without administration of the SIRT1 inhibitor EX527 in the CLP model and lung ECs in vitro were developed to identify mitophagy mechanisms that underlie the cross-talk between SIRT1 signaling and sepsis-induced ALI.
SIRT1 deficient mice exhibited exacerbated sepsis-induced ALI. Knockdown of SIRT1 interfered with mitophagy through late endosome Rab7, leading to the accumulation of damaged mitochondria and inducing excessive mitochondrial reactive oxygen species (mtROS) generation and cytosolic release of mitochondrial DNA (mtDNA), which triggered NLRP3 inflammasome and the cytosolic nucleotide sensing pathways (STING) over-activation. Pharmacological inhibition of STING and NLRP3 i n vivo or genetic knockdown in vitro reversed SIRT1 deficiency mediated endothelial permeability defects and endothelial inflammation in sepsis-induced ALI. Moreover, activation of SIRT1 with SRT1720 in vivo or overexpression of SIRT1 in vitro protected against sepsis-induced ALI.
These findings suggest that SIRT1 signaling is essential for restricting STING and NLRP3 hyperactivation by promoting endosomal-mediated mitophagy in lung ECs, providing potential therapeutic targets for treating sepsis-induced ALI.
急性肺损伤（ALI）是脓毒症患者死亡的主要原因，其原因是促炎内皮变化和内皮通透性缺陷。线粒体功能障碍被认为是脓毒症诱导的 ALI 发病机制中的关键介质。尽管线粒体自噬调节线粒体质量已得到广泛认可，但对于其在脓毒症诱导的 ALI 中肺内皮细胞（ECs）中的作用却知之甚少。Sirtuin 1（SIRT1）是一种组蛋白去乙酰化酶，参与炎症、线粒体自噬和细胞衰老。在这里，作者展示了一种晚期内体依赖性线粒体自噬，它通过 SIRT1 信号在脓毒症诱导的 ALI 中抑制 NLRP3 和 STING 的激活。
建立了 C57BL/6J 雄性小鼠 CLP 模型和体外肺 ECs 模型，以确定 SIRT1 信号与脓毒症诱导的 ALI 之间相互作用的线粒体自噬机制，这些小鼠接受或不接受 SIRT1 抑制剂 EX527 的治疗。
SIRT1 缺陷小鼠表现出脓毒症诱导的 ALI 加重。SIRT1 的敲低通过晚期内体 Rab7 干扰线粒体自噬，导致受损线粒体的积累，并诱导过度的线粒体活性氧（mtROS）生成和线粒体 DNA（mtDNA）的细胞质释放，从而触发 NLRP3 炎性小体和细胞质核苷酸感应途径（STING）过度激活。体内抑制 STING 和 NLRP3 或体外基因敲低逆转了 SIRT1 缺陷介导的脓毒症诱导的 ALI 中的内皮通透性缺陷和内皮炎症。此外，体内用 SRT1720 激活 SIRT1 或体外过表达 SIRT1 可防止脓毒症诱导的 ALI。
这些发现表明，SIRT1 信号对于通过促进肺 ECs 中的晚期内体介导的线粒体自噬来限制 STING 和 NLRP3 的过度激活是必不可少的，为治疗脓毒症诱导的 ALI 提供了潜在的治疗靶点。
