Macrophage Extracellular Traps Aggravate Iron Overload-Related Liver Ischemia/Reperfusion Injury.

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Macrophages regulate iron homeostasis in the liver and play important role in hepatic ischemia/reperfusion (I/R) injury. The aim of this study was to explore the role of macrophages in iron overload-related hepatocyte damage during liver I/R.Liver biopsys 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 then used to explore the interaction between macrophages and ferroptosis. AML12 hepatocytes and RAW264.7 macrophages were co-cultured in vitro and an inhibitor of METs was used to evaluate the role and mechanism of METs and ferroptosis in hepatic I/R injury.Hepatocyte MET formation and ferroptosis were greater in patients who underwent hepatectomy with hepatic portal occlusion and in mice subjected to hepatic I/R. METs increased when macrophages were subjected to hypoxia/reoxygenation, and when METs were co-cultured with hepatocytes, ferroptosis increased and post-hypoxic hepatocyte survival decreased, which were reversed by the inhibition of METs. Ferroptosis inhibition attenuated post-ischemic liver damage. Moreover, iron overload induced hepatic ferroptosis and exacerbated post-ischemic liver damage, which were reversed by the iron chelator.Our results reveal that METs play in regulating ferroptosis and highlight the therapeutic potential of METs and ferroptosis inhibition in reducing liver I/R injury.

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Authors: Shan Wu, Jing Yang, Guoliang Sun, Jingping Hu, Qian Zhang, Jun Cai, Dongdong Yuan, Haobo Li, Ziqing Hei, Weifeng Yao