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

Abstract

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 cocultured 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 cocultured 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.

Verbenalin attenuates hepatic damage and mitochondrial dysfunction in alcohol-associated steatohepatitis by regulating MDMX/PPARα-mediated ferroptosis

“…A growing body of evidence suggests that ferroptosis may serve as a promising target for the prevention and treatment of ASH. Ferroptosis, an iron-dependent form of nonapoptotic cell death (Li et al, 2020), occurs through an increase in cellular phospholipid peroxidation in the context of a compromised phospholipid peroxide repair system (Wang et al, 2021;Wu et al, 2021b). With respect to ASH, liver cells are more susceptible to ferroptosis.…”

Targeting the Hepatic Microenvironment to Improve Ischemia/Reperfusion Injury: New Insights into the Immune and Metabolic Compartments

“…Interestingly, it was found that macrophage extracellular trap was increased in co-cultured experiment subjected to IRI. Moreover, macrophage extracellular trap aggravated ferroptosis, thereby causing an increasing post-ischemia liver damage [ 71 ].…”

High Dietary Organic Iron Supplementation Decreases Growth Performance and Induces Oxidative Stress in Broilers

“…On day 21 and 42, the contents of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total protein (TP), creatinine (CREA), urea nitrogen (UN), glucose (GLU), total antioxidant capacity (T-AOC), catalase (CAT), and malondialdehyde (MDA) in serum were measured by the corresponding commercial kits purchased from Nanjing Jiancheng Bioengineering institute (Nanjing, China), according to the manufacturer's instructions. Serum Fe contents were detected according to the method reported by Wu et al [24]. The serum biochemical parameters with the corresponding commercial kit number are listed in Table 2.…”