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Review
. 2021 Aug 18:12:701163.
doi: 10.3389/fimmu.2021.701163. eCollection 2021.

VSports最新版本 - Ferroptosis: A Trigger of Proinflammatory State Progression to Immunogenicity in Necroinflammatory Disease

Jing-Yan Li  1 , Yong-Ming Yao  1   2 , Ying-Ping Tian  1
Affiliations
Review

Ferroptosis: A Trigger of Proinflammatory State Progression to Immunogenicity in Necroinflammatory Disease

"V体育官网入口" Jing-Yan Li et al. Front Immunol. .

Abstract

Until recently, necrosis is generally regarded as traumatic cell death due to mechanical shear stress or other physicochemical factors, while apoptosis is commonly thought to be programmed cell death, which is silent to immunological response VSports手机版. Actually, multiple modalities of cell death are programmed to maintain systematic immunity. Programmed necrosis, such as necrosis, pyroptosis, and ferroptosis, are inherently more immunogenic than apoptosis. Programmed necrosis leads to the release of inflammatory cytokines, defined as danger-associated molecular patterns (DAMPs), resulting in a necroinflammatory response, which can drive the proinflammatory state under certain biological circumstances. Ferroptosis as a newly discovered non-apoptotic form of cell death, is characterized by excessive lipid peroxidation and overload iron, which occurs in cancer, neurodegeneration, immune and inflammatory diseases, as well as ischemia/reperfusion (I/R) injury. It is triggered by a surplus of reactive oxygen species (ROS) induced in an imbalanced redox reaction due to the decrease in glutathione synthesis and inaction of enzyme glutathione peroxidase 4 (GPX4). Ferroptosis is considered as a potential therapeutic and molecular target for the treatment of necroinflammatory disease, and further investigation into the underlying pathophysiological characteristics and molecular mechanisms implicated may lay the foundations for an interventional therapeutic strategy. This review aims to demonstrate the key roles of ferroptosis in the development of necroinflammatory diseases, the major regulatory mechanisms involved, and its potential as a therapeutic target. .

Keywords: ferroptosis; immune cell; immunogenicity; inflammatory response; necroinflammatory diseases V体育安卓版. .

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

"V体育ios版" Figures

Figure 1
Figure 1
The distinctions between apoptosis and necrosis. On account of the stimuli and context, cells can undergo apoptosis and necrosis. Apoptosis is thought to be programmed cell death relating to homeostasis while necrosis is induced by mechanical shear stress or other physicochemical factors including infection and oxidation, etc. Upon the stimulation of damaged signals, cells trigger programmed necrosis, such as necroptosis, pyroptosis and ferroptosis. Cells suffering from stress may release immunogenic molecules called DAMPs, which could initiate the systematic immune response against detrimental substances, ultimately leading to inflammation. HMGB1, high mobility group box-1 protein; DAMPs, danger-associated molecular patterns.
Figure 2
Figure 2
The mainly regulated mechanism underlying ferroptosis. GPX4 regarded as the key regulator in ferroptosis relies on the biosynthesis of GSH. It produces an antioxidative effect on ferroptotic process, and is regulated by MAV signaling pathway. Xc- system that is composed of SLC7A11 and SLC3A2 regulates ferroptosis together with glutathione metabolic pathway by exchanging glutamate and cystine at 1:1 ratio. Ferroptosis is dependent on overload iron that ascribes to peroxides and divalent ferrous salts produced by fenton reaction. Iron can be transported from extracellular to intracellular in virtue of transferring protein. Mitochondria as the essential organ involving in ferroptosis, contains six ferroptosis-related genes and releases ferroptosis-induced lipid peroxides through the electron-transporting chain. PUFAs, polyunsaturated fatty acids; GSH, glutathione; GPX4, glutathione peroxidase 4; DMT1, divalent metal transporter 1; HSPB1, heat shock protein B1; FTH, ferritin heavy polypeptide; IREB2, iron response element binding protein 2; NRF2, nuclear factor erythroid-2-related factor 2; SLC7A11, transmembrane protein transporter vector family 7 member 11; SLC3A2, single-channel transmembrane regulatory protein solute carrier family 3 member2.
Figure 3
Figure 3
Ferroptosis is critically involved in the development of necroinflammatory diseases. Genetically programmed necrosis is initiated by variously systematic stress including oxidation, immunogenic molecules, metabolic disturbance, and ischemia/reperfusion injury. In the setting of oxidative stress, ferroptosis-induced lipid peroxidation and ROS can promote the programmed necrotic cells to release DAMPs as well as inflammatory cytokines that stimulate innate immune cells to enhance necroinflammatory response. DAMPs, danger-associated molecular patterns; ROS, reactive oxygen species.
Figure 4
Figure 4
GPX4 regulates necroinflammation via arachidonic acid metabolism in ferroptosis. Peroxidized lipids and imbalanced metabolic arachidonic acid (AA) are comprised in ferroptotic process, which exerts an regulatory impact on the process of necroinflammatory response. Upregulation of GPX4 might results in a reduction in the cellular lipid hydroperoxide level, which inactivates PTGS and LOX, eventually inhibiting eicosanoid synthesis. The antioxidative enzyme GPX4 alleviates inflammatory response through eliminating oxidative materials produced in AA metabolism, and regulates the inflammatory state by modulating LOX and PTGS activity in ferroptosis. GSH, reduced glutathione; GSSG, oxidized glutathione; LOX, lipoxygenase; GPX4, glutathione peroxidase 4; H2O2, hydrogen peroxide; PGG2, prostaglandin G2; PTGS, prostaglandin-endoperoxide synthase; HPETE, hydroperoxyeicosatetraenoic acid; (P)LOOH, (phospho) lipid hydroperoxide; PUFA, polyunsaturated fatty acid; AA, arachidonic acid.
Figure 5
Figure 5
GPX4 regulates necroinflammation by inhibiting TNF-α-mediated NF-κB signaling. TNF-α regulates cell survival and death by activating the key transcription factor of NF-κB. NF-κB signal activation, as a downstream promoter element of TNF-α, is negatively suppressed in intracellular survival signaling. Inversely, TNF-α-mediated NF-κB signaling can be markedly activated when ROS is produced in mitochondria. GPX4 can attenuate the necroinflammatory response and suppress the inflammatory cytokines by down-regulating TNF-α-mediated NF-κB signaling pathway. ROS, reactive oxygen species; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; FAD/FADH, flavin adenine dinucletide; NADP/NADPH, nicotinamide adenine dinucleotide phosphate; NF-KB, nuclear factor κB; IκBα, inhibitor of NF-κB α; TNF-α, tumor necrosis factor-α; LT, leukotriene; COX, cyclooxygenase; NOS, nitric oxide synthase.
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