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  • The regulatory effects of NADPH oxidase on ferroptosis might


    The regulatory effects of NADPH oxidase on ferroptosis might also relate to neuroinflammation. Although ferroptosis can trigger inflammatory responses in the brain, neuroinflammation, in turn, can also modify ferroptosis. It has been reported that inflammatory conditions such as those found in neurodegenerative diseases can affect iron homeostasis through transcriptional modification of iron transporters. In Urrutia et al’s study, endotoxin LPS and pro-inflammatory cytokines, such as TNFα and IL-6 were found be able to up-regulate divalent metal transporter 1 (DMT1) mRNA and protein levels and induce a transient decrease in Fpn-1 protein, thus generating an increment of iron content in neurons and microglia (Urrutia et al., 2013). Similar findings were observed in primary midbrain neurons treated with TNFα or IL-1β (Wang et al., 2013). Furthermore, in a LPS-induced Parkinsonian rat model, proinflammatory cytokines released from activated microglia enhanced iron deposits and reduction of Fpn-1 in the substantia nigra (Zhang et al., 2014b). Mechanistic study revealed that NF-κB activation was critical for the elevated expressions of iron transporters and related iron uptake induced by proinflammatory cytokines (Urrutia et al., 2014). NADPH oxidase activation not only produces extracellular superoxide but also elevates intracellular ROS thought to be important secondary messengers that regulate microglial activation and related several pro-inflammatory signaling pathways including NF-κB (Block et al., 2007; Lambeth, 2004). In the present study, inhibition of NADPH oxidase by apocynin suppressed P + M-induced microglial activation, proinflammatory cytokines production and related activation of NF-κB pathway.
    Conflict of interest
    Introduction Ferroptosis, an iron-dependent form of regulated necrosis, has emerged as a new cell death modality highly relevant to disease (Angeli et al., 2017, Gao and Jiang, 2018, Stockwell et al., 2017, Yang and Stockwell, 2016). Ferroptosis results from the accumulation of cellular reactive oxygen species (ROS) that exceed the redox contents maintained by glutathione (GSH) and the phospholipid hydroperoxidases that use GSH as a substrate. The synthetic, small molecule MPC 6827 hydrochloride erastin can trigger ferroptosis by inhibiting the activity of cystine-glutamate antiporter (system Xc−), leading to the depletion of cellular cysteine and GSH, thus the collapse of cellular redox homeostasis (Dixon et al., 2012). Importantly, it is the lipid ROS/peroxides, rather than cytosolic ROS, that unleash ferroptosis. As such, inactivation of glutathione peroxidase 4 (GPX4), an enzyme required for the clearance of lipid ROS, can induce ferroptosis even when cellular cysteine and GSH contents are normal (Friedmann Angeli et al., 2014, Ingold et al., 2018, Yang et al., 2014). Although the physiological function of ferroptosis is still elusive, its involvement in multiple human diseases has been established. Ferroptosis is a major mechanism for cell death associated with ischemic organ injury, including ischemic heart diseases, brain damage, and kidney failure (Friedmann Angeli et al., 2014, Gao et al., 2015a, Linkermann et al., 2014). A role of ferroptosis in neurodegeneration has also been implicated (Chen et al., 2015, Do Van et al., 2016, Skouta et al., 2014). In cancer, ferroptosis has been shown to contribute to the tumor suppressive function of p53 (Galluzzi et al., 2015, Jennis et al., 2016, Jiang et al., 2015, Wang et al., 2016). Many types of cancer cells that are resistant to chemotherapy and certain targeted therapies appear to be sensitive to ferroptosis induced by GPX4 inhibition (Hangauer et al., 2017, Viswanathan et al., 2017). These findings suggest that modulating ferroptosis might be potential therapeutic approaches in treating cancer or other diseases. Cellular metabolism is essential for ferroptosis, presumably because lipid ROS is mainly generated from various steps of cellular metabolism. Mounting evidence has demonstrated that diverse cellular metabolic processes, including lipid metabolism and amino acid metabolism (particularly that involves cysteine and glutamine), contribute to ferroptosis (Gao and Jiang, 2018, Stockwell et al., 2017). Interestingly, the stress-responsive catabolic pathway, autophagy, can also promote ferroptosis by degrading iron-storage protein ferritin and thus increase cellular iron concentration (Gao et al., 2016, Hou et al., 2016). Iron, as an essential cofactor of a plethora of metabolic enzymes and as a catalyst of lipid peroxide-generating Fenton reaction, drives oxygen and redox-based metabolism and cellular ROS production.