Macrophage extracellular traps aggravate iron overload-related liver ischaemia/reperfusion injury


S.Wu, J. Yang, G. Sun, J. Hu, Q. Zhang, J. Cai, D. Yuan, H. Li, Z. Hei, and W. Yao. 2021. “Macrophage extracellular traps aggravate iron overload-related liver ischaemia/reperfusion injury.” Br J Pharmacol, 178, Pp. 3783-3796.


BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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.


1476-5381Wu, ShanYang, JingSun, GuoliangHu, JingpingZhang, QianCai, JunYuan, DongdongLi, HaoboHei, ZiqingYao, WeifengOrcid: 0000-0002-5284-9159Journal ArticleResearch Support, Non-U.S. Gov'tEngland2021/05/08Br J Pharmacol. 2021 Sep;178(18):3783-3796. doi: 10.1111/bph.15518. Epub 2021 Jun 13.