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Review
. 2019 Jan;26(1):14-24.
doi: 10.1038/s41418-018-0173-9. Epub 2018 Aug 6.

Ferroptosis and necroinflammation, a yet poorly explored link

Bettina Proneth  1 , Marcus Conrad  2
Affiliations
Review

Ferroptosis and necroinflammation, a yet poorly explored link (V体育平台登录)

Bettina Proneth et al. Cell Death Differ. 2019 Jan.

Abstract

Ferroptosis is a non-apoptotic form of cell death characterized by overwhelming iron-dependent lipid peroxidation, which contributes to a number of pathologies, most notably tissue ischemia/reperfusion injury, neurodegeneration and cancer. Cysteine availability, glutathione biosynthesis, polyunsaturated fatty acid metabolism and modulation of the phospholipidome are the key events of this necrotic cell death pathway VSports手机版. Non-enzymatic and enzymatic lipoxygenase (LOX)-mediated lipid peroxidation of lipid bilayers is efficiently counteracted by the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis. Preliminary studies suggest that bursting ferroptotic cells release pro-inflammatory damage-associated molecular patterns (DAMPs) that trigger the innate immune system as exemplified by diseased kidney and brain tissues where ferroptosis contributes to organ demise in a predominant manner. The GSH/GPX4 node is known to control the activities of LOX and prostaglandin-endoperoxide synthase (PTGS) via the so-called peroxide tone. Since LOX and PTGS products do have pro- and anti-inflammatory effects, one may speculate that these enzymes contribute to the ferroptotic process on several levels in cell-autonomous and non-autonomous ways. Hence, this review provides the reader with an outline on what is currently known about the link between ferroptosis and necroinflammation and discusses critical events that may alert the innate immune system in early phases when cells become sensitized towards ferroptosis. .

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"V体育官网" Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
The core mechanisms controlling ferroptotic cell death. System xc- (a heterodimeric amino acid transporter consisting of 4F2 heavy chain and xCT (SLC7A11) light chain—the latter is shown) is responsible for the uptake of extracellular cystine. Cysteine can also be taken up by the neutral amino acid transporter ASC (not shown), which is highly relevant for in vivo conditions. Cysteine is the substrate-limiting step for glutathione biosynthesis. GSH provides electrons to the key regulator of ferroptosis, GPX4, which is one of the most efficient enzymes in reducing lipid peroxides (–OOH) in membranes to the corresponding alcohols (–OH). Recently, additional enzymes, such as ACSL4 and LPCAT that are directly involved in shaping the cellular phospholipidome, have been added to the list of enzymes contributing to ferroptosis. Oxidation of lipid bilayers during ferroptosis may occur both in an enzymatic (i.e. LOX) and non-enzymatic, autoxidative manner (i.e. radical-mediated; symbolized by the red arrow). Ferroptosis inhibitors are depicted by green boxes, whereas ferroptosis-inducing agents are marked by red boxes. ACSL4 acyl-CoA synthetase long-chain family member 4, GPX4 glutathione peroxidase 4, GSH reduced glutathione, GSSG oxidized glutathione, LOX lipoxygenase, LPCAT lysophosphatidylcholine acyltransferase, PUFA polyunsaturated fatty acid, BSO L-buthionine-sulfoximine
Fig. 2
Fig. 2
Ferroptotic kidney tubular cells release cell debris and nuclei that in turn activate the innate immune system. Tamoxifen-inducible whole body GPX4 knockout mice die around two weeks after knockout induction due to massive cell death of kidney tubular cells and associated acute renal failure (see Ref. [15]). Bursting tubular cells release cellular debris including mitochondria (blue arrows) and nuclei into the lumen of kidney proximal tubules (red arrows). F4/80 immunostaining reveals massive activation of macrophages in diseased tissue. Micrographs adopted and modified from Friedmann Angeli et al. 2014 [15]. F4/80 adhesion G protein-coupled receptor E1, TEM transmission electron microscopy
Fig. 3
Fig. 3
Arachidonate metabolizing enzymes are controlled by the peroxide tone. Oxidation of heme and non-heme containing enzymes PTGS and LOX enzymes, respectively, by cellular peroxides is essential for full activity. Since the GSH/GPX4 node controls cellular lipid peroxides, the entire PTGS/LOX axis is indirectly regulated by this system. 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
Fig. 4
Fig. 4
The GSH/GPX4 and LOX/PTGS systems may modulate the ferroptotic process on several levels. Since GPX4 and LOX (PTGS) are not only directly involved in the ferroptotic process by determining the levels of peroxides in ferroptosis-relevant phosphatidylethanolamine-containing arachidonic and adrenic acids (left), but also in the generation of HPETEs, HPODE (and its further downstream products) and prostaglandins (right), they may also contribute to the early process of innate immune cell activation. This in turn could spark a vicious cycle by negatively impacting on GPX4 expression levels. AA arachidonic acid, AdA adrenic acid, ACSL4 acyl-CoA synthetase long-chain family member 4, GPX4 glutathione peroxidase 4, H2O2 hydrogen peroxide, HPETE hydroperoxyeicosatetraenoic acid, HPODE hydroperoxylinoleic acid, LOX lipoxygenase, LPCAT lysophosphatidylcholine acyltransferase, (P)LOOH (phospho)lipid hydroperoxide, PE phosphatidylethanolamine, PTGS prostaglandin-endoperoxide synthase, TNFα tumor necrosis factor α
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