Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China.
Hepatol Commun. 2024 Mar 18;8(4). doi: 10.1097/HC9.0000000000000399. eCollection 2024 Apr 1.
Fatty livers are widely accepted as marginal donors for liver transplantation but are more susceptible to liver ischemia and reperfusion (IR) injury. Increased macrophage-related inflammation plays an important role in the aggravation of fatty liver IR injury. Here, we investigate the precise mechanism by which endoplasmic reticulum (ER) stress activates macrophage NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling by regulating mitochondrial calcium overload in fatty liver IR.
Control- and high-fat diet-fed mice were subjected to a partial liver IR model. The ER stress, mitochondrial calcium levels, and NLRP3 signaling pathway in macrophages were analyzed.
Liver steatosis exacerbated liver inflammation and IR injury and enhanced NLRP3 activation in macrophages. Myeloid NLRP3 deficiency attenuated intrahepatic inflammation and fatty liver injury following IR. Mechanistically, increased ER stress and mitochondrial calcium overload were observed in macrophages obtained from mouse fatty livers after IR. Suppression of ER stress by tauroursodeoxycholic acid effectively downregulated mitochondrial calcium accumulation and suppressed NLRP3 activation in macrophages, leading to decreased inflammatory IR injury in fatty livers. Moreover, Xestospongin-C-mediated inhibition of mitochondrial calcium influx decreased reactive oxygen species (ROS) expression in macrophages after IR. Scavenging of mitochondrial ROS by mito-TEMPO suppressed macrophage NLRP3 activation and IR injury in fatty livers, indicating that excessive mitochondrial ROS production was responsible for macrophage NLRP3 activation induced by mitochondrial calcium overload. Patients with fatty liver also exhibited upregulated activation of NLRP3 and the ER stress signaling pathway after IR.
Our findings suggest that ER stress promotes mitochondrial calcium overload to activate ROS/NLRP3 signaling pathways within macrophages during IR-stimulated inflammatory responses associated with fatty livers.
脂肪肝被广泛认为是肝移植的边缘供体，但更容易发生肝缺血再灌注（IR）损伤。巨噬细胞相关炎症增加在脂肪肝 IR 损伤的加重中起着重要作用。在这里，我们研究内质网（ER）应激通过调节脂肪肝 IR 中线粒体钙超载激活巨噬细胞 NOD 样受体热蛋白结构域相关蛋白 3（NLRP3）信号的精确机制。
对对照饮食喂养和高脂肪饮食喂养的小鼠进行部分肝 IR 模型。分析巨噬细胞中的 ER 应激、线粒体钙水平和 NLRP3 信号通路。
肝脂肪变性加剧了肝炎症和 IR 损伤，并增强了巨噬细胞中 NLRP3 的激活。髓样 NLRP3 缺陷减轻了 IR 后肝内炎症和脂肪肝损伤。机制上，IR 后从小鼠脂肪肝中获得的巨噬细胞中观察到 ER 应激增加和线粒体钙超载。牛磺熊脱氧胆酸抑制 ER 应激可有效下调巨噬细胞中线粒体钙积累并抑制 NLRP3 激活，从而减少脂肪肝的炎症性 IR 损伤。此外，Xestospongin-C 介导的抑制线粒体钙内流可降低 IR 后巨噬细胞中活性氧（ROS）的表达。通过 mito-TEMPO 清除线粒体 ROS 可抑制巨噬细胞 NLRP3 激活和脂肪肝 IR 损伤，表明过量的线粒体 ROS 产生是线粒体钙超载诱导巨噬细胞 NLRP3 激活的原因。脂肪肝患者在 IR 后也表现出 NLRP3 和 ER 应激信号通路的上调激活。
我们的研究结果表明，ER 应激通过在 IR 刺激的与脂肪肝相关的炎症反应期间激活巨噬细胞中线粒体钙超载来促进 ROS/NLRP3 信号通路。
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