Ferroptosis and necroinflammation, a yet poorly explored link

Proneth, Bettina; Conrad, Marcus

doi:10.1038/s41418-018-0173-9

Cited by 262 publications

(217 citation statements)

References 90 publications

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“…Indeed, we observed that I/R upregulated the expression of inflammatory cytokines in the liver, which was prevented by Fer‐1, suggesting that ferroptosis‐mediated cell death is an upstream event for inflammatory responses during hepatic I/R injury. Recently, inflammation induced by cell death in a necrotic manner has been referred to as “necroinflammation.” In particular, ferroptosis‐induced necroinflammation has received considerable attention . In this scenario, hepatic I/R causes hepatocyte ferroptosis and triggers extracellular release of cellular contents known as damage‐associated molecular patterns, which are in turn recognized by pattern recognition receptors including Toll‐like receptors or Nod‐like receptors on Kupffer cells and endothelial cells, and eventually induce inflammatory responses and enhance liver damage.…”

Section: Discussionmentioning

confidence: 99%

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Yamada

Karasawa

Wakiya

et al. 2020

American Journal of Transplantation

181

130

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Hepatic ischemia-reperfusion (I/R) injury is a major problem in liver transplantation (LT). Although hepatocyte cell death is the initial event in hepatic I/R injury, the underlying mechanism remains unclear. In the present study, we retrospectively analyzed the clinical data of 202 pediatric living donor LT and found that a high serum ferritin level, a marker of iron overload, of the donor is an independent risk factor for liver damage after LT. Since ferroptosis has been recently discovered as an iron-dependent cell death that is triggered by a loss of cellular redox homeostasis, we investigated the role of ferroptosis in a murine model of hepatic I/R injury, and found that liver damage, lipid peroxidation, and upregulation of the ferroptosis marker Ptgs2 were induced by I/R, and all of these manifestations were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or α-tocopherol. Fer-1 also inhibited hepatic I/R-induced inflammatory responses. Furthermore, hepatic I/R injury was attenuated by iron chelation by deferoxamine and exacerbated by iron overload with a high iron diet. These findings demonstrate that iron overload is a novel risk factor for hepatic I/R injury in LT, and ferroptosis contributes to the pathogenesis of hepatic I/R injury. K E Y W O R D Scell death, liver transplantation/hepatology, liver transplantation: living donor, translational research/science

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Section: Discussionmentioning

confidence: 99%

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Yamada

Karasawa

Wakiya

et al. 2020

American Journal of Transplantation

181

130

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“…Similar to other types of regulated necrosis such as necroptosis and pyroptosis, ferroptosis leads to complete plasma membrane disruption and the final bursting of the cell (Dixon et al, 2012, Proneth & Conrad, 2019. Increase in cytosolic Ca 2+ , cell swelling, rounding, as well as plasma membrane breakdown have been described as hallmarks for necroptosis and pyroptosis, which represent critical differences to apoptosis (Frank & Vince, 2018, Ros et al, 2017, Vandenabeele, Galluzzi et al, 2010.…”

Section: Sustained Increase In Cytosolic Ca 2+ Is a Hallmark Of Ferromentioning

confidence: 97%

“…Ferroptosis is a caspase-independent form of regulated cell death characterized by the generation of lethal amounts of iron-dependent lipid hydroperoxides in cellular membranes (Dixon, Lemberg et al, 2012. Cells dying via ferroptosis are characterized by plasma membrane rupture and release of otherwise confined intracellular components including pro-inflammatory damage-associated molecular patterns (DAMPs) (Proneth & Conrad, 2019).…”

Section: Introductionmentioning

confidence: 99%

Ferroptotic pores induce Ca²⁺ fluxes and ESCRT-III activation to modulate cell death kinetics

Pedrera

Espiritu

Ros

et al. 2019

Preprint

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Ferroptosis is an iron-dependent form of regulated necrosis associated with lipid peroxidation. Despite its key role in the inflammatory outcome of ferroptosis, little is known about the molecular events leading to the disruption of the plasma membrane during this type of cell death. Here we show that a sustained increase in cytosolic Ca 2+ is a hallmark of ferroptosis that precedes complete bursting of the cell. We report that plasma membrane damage leading to ferroptosis is associated with membrane nanopores of few nanometers in radius and that ferroptosis, but not lipid peroxidation, can be delayed by osmoprotectants. Importantly, Ca 2+ fluxes during ferroptosis correlate with the activation of ESCRT-III-mediated membrane repair, which counterbalances the kinetics of cell death and modulates the inflammatory signature of ferroptosis. Our findings with ferroptosis provide a unifying concept that sustained high levels of cytosolic Ca 2+ prior to plasma membrane disruption are a common feature of regulated necrosis and position ESCRT-III as a general protective mechanism in these inflammatory cell death pathways.

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“…Ferroptosis is a mode of programmed cell death that is characterized by an iron-dependent accumulation of lipid peroxides [48]. Interestingly, ferroptosis is considered to be pro-inflammatory and immunogenic, due to release of damage-associated molecular patterns (DAMPs) [67,68]. Hence, besides the direct effects on the tumor cells, artesunate may also support anti-tumor immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, besides the direct effects on the tumor cells, artesunate may also support anti-tumor immune responses. However, direct evidence for this possibility is still scarce and further investigations on this topic are necessary [67]. Notwithstanding, following preclinical evaluation of the anti-tumoral activity of artesunate in recent years, we have now reached a phase of human trials for the treatment of cancer patients with artesunate.…”

Section: Discussionmentioning

confidence: 99%

Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

Sarma

Willmes

Angerer

et al. 2020

Cancers

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Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate-a drug used to treat malaria-has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and β-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy.Cancers 2020, 12, 919 2 of 15 cells [6], and subsequent studies confirmed that approximately 80% of all MCC cases are associated with MCPyV [7]. Importantly, the integration patterns suggest that clonal expansion of the tumor cells occurs after MCPyV integration sustaining the assumption that viral proteins are causal for tumorigenesis [6,8,9]. Moreover, in MCPyV-positive MCC cells, expression of the viral oncoproteins small and Large T-antigen (sT and LT) can be detected, and these proteins are essential for growth of the tumor cells [10,11] qualifying them as potential therapeutic targets.The five-year overall survival rate for patients with MCC is only about 40%, although the relative survival rate (compared to an age-and sex-matched population) is 54% [12]. Primary MCCs are excised by surgery, and adjuvant radiotherapy of the primary tumor location and the lymph node region is recommended [13]. Until recently, the metastatic disease was treated preferentially with various, not-standardized chemotherapeutic regimens, all of which could not improve survival of the patients significantly [14]. Recently, however, antibodies targeting the immune suppressive protein programmed cell death protein 1 (PD-1) or its ligand PD-L1 have demonstrated high response rates of 56 in first-line and 32% in second-line treatment, respectively for patients with stage IV disease [15,16]. Indeed, the PD-L1 targeting antibody Avelumab was the first treatment for metastatic MCC approved both in the US and European Union [17]. Importantly, data avail...

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Ferroptosis and necroinflammation, a yet poorly explored link

Cited by 262 publications

References 90 publications

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Ferroptotic pores induce Ca²⁺ fluxes and ESCRT-III activation to modulate cell death kinetics

Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

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Ferroptosis and necroinflammation, a yet poorly explored link

Cited by 262 publications

References 90 publications

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics

Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

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Ferroptotic pores induce Ca²⁺ fluxes and ESCRT-III activation to modulate cell death kinetics