Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Department of Anesthesiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
Br J Pharmacol. 2021 Sep;178(18):3783-3796. doi: 10.1111/bph.15518. Epub 2021 Jun 13.
Macrophages regulate iron homeostasis in the liver and play important role in hepatic ischaemia/reperfusion (I/R) injury. This study investigates the role of macrophages in iron overload-related hepatocyte damage during liver I/R.
Liver biopsies from patients undergoing partial hepatectomy with or without hepatic portal occlusion were recruited and markers of hepatocyte cell death and macrophage extracellular traps (METs) were detected. A murine hepatic I/R model was also established in high-iron diet-fed mice. Ferrostatin-1 and deferoxamine were administered to investigate the role of ferroptosis in hepatic I/R injury. The macrophage inhibitor liposome-encapsulated clodronate was used to investigate the interaction between macrophages and ferroptosis. AML12 hepatocytes and RAW264.7 macrophages were co-cultured in vitro. An inhibitor of macrophage extracellular traps was used to evaluate the role and mechanism of these traps and ferroptosis in hepatic I/R injury.
Hepatocyte macrophage extracellular trap formation and ferroptosis were greater in patients who underwent hepatectomy with hepatic portal occlusion and in mice subjected to hepatic I/R. Macrophage extracellular traps increased when macrophages were subjected to hypoxia/reoxygenation and when they were co-cultured with hepatocytes. Ferroptosis increased and post-hypoxic hepatocyte survival decreased, which were reversed by inhibition of macrophage extracellular traps. Ferroptosis inhibition attenuated post-ischaemic liver damage. Moreover, iron overload induced hepatic ferroptosis and exacerbated post-ischaemic liver damage, which were reversed by the iron chelator.
Macrophage extracellular traps are in volved in regulating ferroptosis highlighting the therapeutic potential of macrophage extracellular traps and ferroptosis inhibition in reducing liver I/R injury.
巨噬细胞调节肝脏中的铁稳态，并在肝缺血/再灌注（I/R）损伤中发挥重要作用。本研究探讨巨噬细胞在肝脏 I/R 期间铁过载相关肝细胞损伤中的作用。
招募行部分肝切除术伴或不伴肝门阻断的患者肝活检，并检测肝细胞死亡和巨噬细胞细胞外陷阱（METs）的标志物。还在高铁饮食喂养的小鼠中建立了肝 I/R 模型。给予铁抑素-1 和去铁胺以研究铁死亡在肝 I/R 损伤中的作用。使用包裹氯膦酸盐的脂质体作为巨噬细胞抑制剂来研究巨噬细胞与铁死亡之间的相互作用。体外将 AML12 肝细胞和 RAW264.7 巨噬细胞共培养。使用一种巨噬细胞细胞外陷阱抑制剂来评估这些陷阱和铁死亡在肝 I/R 损伤中的作用和机制。
行肝门阻断的肝切除术患者和肝 I/R 小鼠的肝细胞和巨噬细胞细胞外陷阱形成和铁死亡更为明显。巨噬细胞在经历缺氧/复氧和与肝细胞共培养时，细胞外陷阱增加。铁死亡增加，缺氧后肝细胞存活率降低，而抑制细胞外陷阱可逆转这一现象。铁死亡抑制减轻了缺血后的肝损伤。此外，铁过载诱导肝铁死亡并加重缺血后肝损伤，而铁螯合剂可逆转这一现象。
巨噬细胞细胞外陷阱参与调节铁死亡，这突显了抑制巨噬细胞细胞外陷阱和铁死亡在减轻肝 I/R 损伤中的治疗潜力。
