Ferroptosis in infection, inflammation, and immunity

Chen, Xin; Kang, Rui; Kroemer, Guido; Tang, Daolin

doi:10.1084/jem.20210518

Cited by 448 publications

(270 citation statements)

References 153 publications

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“…These results suggested that ferroptosis inhibition affected viral propagation of MHV-A59. Because ferroptosis often occurs along with inflammatory cytokine release [51], we wanted to determine how ferroptosis inhibition influenced MHV-A59-induced inflamma- Because ferroptosis often occurs along with inflammatory cytokine release [51], we wanted to determine how ferroptosis inhibition influenced MHV-A59-induced inflammation. IL-6 and CXCL-10 were two characterized upregulated cytokines in coronavirus infection [52,53].…”

Section: Ferroptosis Inhibitors Reduced Viral Load and Inflammatory Cytokine Release After Mhv-a59 Infectionmentioning

confidence: 99%

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Xia

Zhang

You

2021

Viruses

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Murine hepatitis virus strain A59 (MHV-A59) was shown to induce pyroptosis, apoptosis, and necroptosis of infected cells, especially in the murine macrophages. However, whether ferroptosis, a recently identified form of lytic cell death, was involved in the pathogenicity of MHV-A59 is unknown. We utilized murine macrophages and a C57BL/6 mice intranasal infection model to address this. In primary macrophages, the ferroptosis inhibitor inhibited viral propagation, inflammatory cytokines released, and cell syncytia formed after MHV-A59 infection. In the mouse model, we found that in vivo administration of liproxstatin-1 ameliorated lung inflammation and tissue injuries caused by MHV-A59 infection. To find how MHV-A59 infection influenced the expression of ferroptosis-related genes, we performed RNA-seq in primary macrophages and found that MHV-A59 infection upregulates the expression of the acyl-CoA synthetase long-chain family member 1 (ACSL1), a novel ferroptosis inducer. Using ferroptosis inhibitors and a TLR4 inhibitor, we showed that MHV-A59 resulted in the NF-kB-dependent, TLR4-independent ACSL1 upregulation. Accordingly, ACSL1 inhibitor Triacsin C suppressed MHV-A59-infection-induced syncytia formation and viral propagation in primary macrophages. Collectively, our study indicates that ferroptosis inhibition protects hosts from MHV-A59 infection. Targeting ferroptosis may serve as a potential treatment approach for dealing with hyper-inflammation induced by coronavirus infection.

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Section: Ferroptosis Inhibitors Reduced Viral Load and Inflammatory Cytokine Release After Mhv-a59 Infectionmentioning

confidence: 99%

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Xia

Zhang

You

2021

Viruses

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“…Nevertheless, a more comprehensive approach is essential to enhance the pro-ferroptotic effect of STING1 without changing its beneficial mechanism in tumor immunity. Since STING1 plays a critical role in innate immunity, it is still interesting whether mitochondrial STING1-mediated ferroptosis is implicated in infection and sterile injury ( Chen et al, 2021b ).…”

Section: Discussionmentioning

confidence: 99%

STING1 Promotes Ferroptosis Through MFN1/2-Dependent Mitochondrial Fusion

Liu

Hou

et al. 2021

Front. Cell Dev. Biol.

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Ferroptosis is a type of iron-dependent regulated cell death caused by the disruption that occurs when oxidative stress and antioxidant defenses interact, and then driven by lipid peroxidation and subsequent plasma membrane ruptures. The regulation of ferroptosis involves many factors, including the crosstalk between subcellular organelles, such as mitochondria, endoplasmic reticulum (ER), lysosomes, lipid droplets, and peroxisomes. Here, we show that the ER protein STING1 (also known as STING or TMEM173) promotes ferroptosis in human pancreatic cancer cell lines by increasing MFN1/2-dependent mitochondrial fusion, but not mitophagy-mediated mitochondrial removal. The classic ferroptosis inducer erastin, but not sulfasalazine, induces the accumulation of STING1 in the mitochondria, where it binds to MFN1/2 to trigger mitochondrial fusion, leading to subsequent reactive oxygen species production and lipid peroxidation. Consequently, in vitro or xenograft mouse models show that the genetic depletion of STING1 or MFN1/2 (but not the mitophagy regulator PINK1 or PRKN) reduces the sensitivity of pancreatic cancer cells to ferroptosis. These findings not only establish a new mitochondrial fusion-dependent cell death mechanism, but also indicate a potential strategy for enhancing ferroptosis-based therapy.

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“…A typical example is represented by the central nervous system that, even in the condition of systemic anemia, maintains constant its own iron quantity [ 130 ]. As for iron overload, independent of the cause, it triggers detrimental processes within cells and the type of cell death induced by iron accumulation has been named ferroptosis [ 131 ]. While it is true that all cell types are affected by iron unbalance, two organs are paradigmatic in the ferroptosis scenario; the heart is one of the principal utilisers of iron while the liver is principally responsible for iron handling.…”

Section: Discussionmentioning

confidence: 99%

Iron Overload, Oxidative Stress, and Ferroptosis in the Failing Heart and Liver

et al. 2021

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Iron accumulation is a key mediator of several cytotoxic mechanisms leading to the impairment of redox homeostasis and cellular death. Iron overload is often associated with haematological diseases which require regular blood transfusion/phlebotomy, and it represents a common complication in thalassaemic patients. Major damages predominantly occur in the liver and the heart, leading to a specific form of cell death recently named ferroptosis. Different from apoptosis, necrosis, and autophagy, ferroptosis is strictly dependent on iron and reactive oxygen species, with a dysregulation of mitochondrial structure/function. Susceptibility to ferroptosis is dependent on intracellular antioxidant capacity and varies according to the different cell types. Chemotherapy-induced cardiotoxicity has been proven to be mediated predominantly by iron accumulation and ferroptosis, whereas there is evidence about the role of ferritin in protecting cardiomyocytes from ferroptosis and consequent heart failure. Another paradigmatic organ for transfusion-associated complication due to iron overload is the liver, in which the role of ferroptosis is yet to be elucidated. Some studies report a role of ferroptosis in the initiation of hepatic inflammation processes while others provide evidence about an involvement in several pathologies including immune-related hepatitis and acute liver failure. In this manuscript, we aim to review the literature to address putative common features between the response to ferroptosis in the heart and liver. A better comprehension of (dys)similarities is pivotal for the development of future therapeutic strategies that can be designed to specifically target this type of cell death in an attempt to minimize iron-overload effects in specific organs.

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Ferroptosis in infection, inflammation, and immunity

Cited by 448 publications

References 153 publications

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

STING1 Promotes Ferroptosis Through MFN1/2-Dependent Mitochondrial Fusion

Iron Overload, Oxidative Stress, and Ferroptosis in the Failing Heart and Liver

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