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Abstract

Microglia play an important role in maintaining central nervous system homeostasis and are the major immune cells in the brain. In response to internal or external inflammatory stimuli, microglia are activated and release numerous inflammatory factors, thus leading to neuroinflammation. Inflammation and microglia iron accumulation promote each other and jointly promote the progression of neuroinflammation. Inhibiting microglia iron accumulation prevents neuroinflammation. Ferroptosis is an iron-dependent phospholipid peroxidation-driven type of cell death regulation. Cell iron accumulation causes the peroxidation of cell membrane phospholipids and damages the cell membrane. Ultimately, this process leads to cell ferroptosis. Iron accumulation or phospholipid peroxidation in microglia releases a large number of inflammatory factors. Thus, inhibiting microglia ferroptosis may be a new target for the prevention and treatment of neuroinflammation.

Keywords

ferroptosis iron accumulation microglia neurodegenerative disease neuroinflammation phospholipid peroxidation

Introduction

Neuroinflammation refers to an inflammatory response within the central nervous system (CNS) that is caused by exogenous and/or endogenous factors (Leng & Edison, 2021; Maccioni et al., 2018). Neuroinflammation shares common features with peripheral inflammation, but the unique glial cells and neurons in the CNS distinguish neuroinflammation from peripheral inflammation (Urrutia et al., 2021). Following CNS injury, early inflammation is beneficial to remove harmful substances and inhibit the development of injury, which is conducive to tissue regeneration and recovery (Russo & McGavern, 2016). However, ongoing neuroinflammation in chronic neurological diseases damages the nervous system (Stephenson et al., 2018). Owing to gradual improvement of the living environment and rapid development of modern medicine, the average life expectancy has been gradually increasing with a corresponding increase in the number of the elderly in society. Increased life expectancy may increase the risk of neuroinflammation-related neurodegenerative diseases. Microglia are the main functional cells that mediate neuroinflammation in the CNS. Activated microglia release inflammatory factors to promote neuroinflammation. Chronic inflammation mediated by microglia has been found to cause damage to healthy neural tissue in neurodegenerative diseases (Subhramanyam et al., 2019). Therefore, interventions that address chronic inflammation mediated by microglia may be a suitable strategy against neurodegenerative diseases (Subhramanyam et al., 2019). Microglia iron accumulation and inflammation have a bidirectional relationship and they jointly promote the progression of neuroinflammation. Ferroptosis is an iron-dependent and phospholipid peroxidation-driven process to regulate cell death (Jiang et al., 2021). Previous studies have shown that ferroptosis is closely related to neuroinflammation (Cao et al., 2021; Cui et al., 2021a; Ko et al., 2021). This article presents a new viewpoint that the prevention and treatment of a number of neurodegenerative diseases can be achieved by inhibiting microglia iron accumulation or microglia ferroptosis.

Microglia and Neuroinflammation

Microglia which originate from primitive macrophages of the embryonic yolk sac are the main immune cells in the CNS (Nayak et al., 2014). Microglia are the first line of defense of the CNS innate immune system (Orihuela et al., 2016). Microglia have important roles in neurogenesis (Xiong et al., 2016), synaptic density, and synaptic plasticity (Colonna & Butovsky, 2017). When the CNS is damaged, microglia are responsible for phagocytosis and clearance of pathological protein aggregates, dead cells, and other pathological particles (Colonna & Butovsky, 2017).

Inflammatory stimuli of lipopolysaccharide (LPS) and interferon γ (IFN γ) activate resting microglia to transform into classically activated M1 type which express the proinflammatory factors interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, leading to CNS damage (Orihuela et al., 2016). IL-4 and IL-13 induce microglia to transform into M2 type which express anti-inflammatory factors such as transforming growth factor-β, IL-4, IL-10, and IL-13 that promote nerve repair and regeneration to maintain CNS homeostasis (Orihuela et al., 2016; Subhramanyam et al., 2019). The morphology of microglia is highly dynamic. Resting microglia that show the branching morphology will polarize to the amoeboid morphology when stimulated (Colonna & Butovsky, 2017). In response to stimulation by different factors, microglia continuously polarize between their phenotypes M1 and M2 (Orihuela et al., 2016). M1 and M2 can be interconverted to maintain CNS internal environment homeostasis.

A study showed that hemoglobin induced microglia to express the anti-inflammatory factor IL-10 (Li et al., 2021b). Subsequently, IL-10 increased the phagocytic capacity of microglia by inducing the expression of leukocyte differentiation antigen 36, which accelerated the clearance of hematoma and reduced neuroinflammation. Another study showed that downregulating the expression of interferon regulatory factor (IRF) 5 in microglia led to the increase of IRF4 expression and M2 type activation in microglia, which released anti-inflammatory factors and ultimately improved stroke prognosis (Al Mamun et al., 2020). Conversely, downregulation of IRF4 expression resulted in the increase of IRF5 expression and M1 type activation, releasing proinflammatory factors (Al Mamun et al., 2020). Therefore, the microglia IRF5-IRF4 regulatory axis regulates neuroinflammation (Al Mamun et al., 2020). Scp2-1, a polysaccharide extracted from Schisandra chinensis, inhibited nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, which significantly reduced M1 type polarization of microglia induced by LPS and promoted the transformation of microglia to M2 type, thus inhibiting neuroinflammation (Xu et al., 2020). The triggering receptor expressed on myeloid cells-1 (TREM-1) expressed on microglia is a transmembrane immune receptor. In a previous study, the interaction between TREM-1 and spleen tyrosine kinase activated the downstream inflammatory pathway and demonstrated that blocking TREM-1 was a target for the treatment of stroke (Xu et al., 2019). In conclusion, microglia are closely related to neuroinflammation (Rodríguez et al., 2022).

Neuroinflammation and Microglia Iron Accumulation

Neuroinflammation Induces Microglia Iron Accumulation

Coculture of heparan sulfate oligosaccharides isolated from the urine of patients with Sanfilippo syndrome (SP) and microglia reduced the content of ferroportin 1 (FPN1) in microglia, leading to microglia iron accumulation and the release of inflammatory factors with a severe neuroinflammatory response (Puy et al., 2018).

Microglia iron accumulation is involved in the occurrence and development of Parkinson's disease (PD). Chronic inflammation in the substantia nigra (SN) was accompanied by progressive neurodegenerative lesions (Thomsen et al., 2015). Significant iron accumulation occurred in microglia and the expression of ferritin (FRN) was significantly increased during the progression of inflammation (Thomsen et al., 2015). Treatment with 6-hydroxydopamine (6-OHDA) induced the expression of divalent metal transporter 1 (DMT1) and iron influx, resulting in iron overload in microglia (Xu et al., 2022). After the injection of 6-OHDA into the rat brain to establish a PD model, a large number of iron-rich microglia appeared in the damaged SN, indicating that microglia iron accumulation was associated with the progression of PD (Olmedo-Díaz et al., 2017). Pathological accumulation of α-synuclein (α-syn) in the brain promoted the progression of PD, and the results of the study indicated that intranasal injection of α-syn preformed fibrils caused iron deposition in microglia, suggesting that microglia iron deposition may be involved in the progression of PD (Guo et al., 2021).

Inflammatory factors and inflammatory substances cause microglia iron accumulation. LPS increased the expression of heme oxygenase-1 (HO-1) in microglia, which catalyzed heme to release Fe²⁺, thereby increasing the content of iron in cells (McCarthy et al., 2018). LPS and β-amyloid (Aβ) separately upregulated the expression of DMT1 and FRN in microglia, increased the uptake of iron by microglia, and led to microglia iron accumulation (McCarthy et al., 2018). LPS treatment and oxygen-glucose deprivation/reperfusion upregulated the expression of hepcidin (Hepc) and FRN in microglia and caused microglia iron accumulation (Shin et al., 2018). Stimulation of microglia by either LPS, TNF-α, or IL-6 promoted the expression of DMT1 and Hepc, and ultimately caused microglia iron accumulation (Urrutia et al., 2013). Simultaneous stimulation with IFNγ and Aβ induced microglia iron accumulation and glycolysis, which increased the content of reactive oxygen species (ROS), TNF-α, and inducible NO synthase (iNOS) in microglia (McIntosh et al., 2019). IFNγ treatment alone also induced microglia iron accumulation and significantly increased the mRNA expression of TNF-α and iNOS (Holland et al., 2018). TNF-α upregulated the expression of DMT1 and downregulated the expression of FPN1 in microglia, thus increasing the uptake of iron and iron retention in microglia (Rathore et al., 2012).

Microglia Iron Accumulation Leads to Neuroinflammation

Microglia iron accumulation aggravates neuroinflammation and the development of PD. A clinical autopsy study found a close link between iron accumulation and microglia proliferation in the SN sections of patients with PD (Martin-Bastida et al., 2021). Microglia exposure to high concentrations of ferric ammonium citrate (FAC) led to iron overload in microglia, which increased the expression of ROS and promoted the release of TNF-α and IL-1β (Angelova & Brown, 2018b). Microglia iron accumulation led to an increased release of TNF-α in microglia and subsequent TNF-α activation of the NF-κB and JNK pathways in SH-SY5Y neurons, resulting in an increased expression of α-syn in SH-SY5Y neurons (Angelova & Brown, 2018b).

Microglia iron accumulation promotes the progression of neuroinflammation and disease in multiple sclerosis (MS). Many iron-rich microglia accumulated around chronic active demyelinating lesions and continuously released proinflammatory factors, leading to tissue damage and MS progression (Gillen et al., 2018). The brain sections of patients with MS showed that iron deposition occurred in the marginal area of MS demyelinating lesions, and the microglia in the marginal area exhibited M1 polarization (Mehta et al., 2013). After macrophages were exposed to ferric chloride in vitro, macrophage iron accumulation drove macrophage transformation into M1 type, leading to the release of proinflammatory factors (Mehta et al., 2013). Studies investigating patient brain sections and in vitro research results showed that the microglia at the edge of chronic active white matter demyelinating lesions accumulated iron, thus promoting the transformation of microglia into M1 type which released proinflammatory factors and resulted in the expansion of the lesion (Mehta et al., 2013). A clinical study showed that in the case of demyelinating lesion with slow expansion, iron-rich microglia accumulated at the edge of the lesion and stayed in an activated state, which promoted the progression of MS (Dal-Bianco et al., 2017). Another clinical study found that a large number of iron-rich microglia accumulated around MS demyelinating lesions, which promoted the progression of MS and demonstrated the potential for the development of more serious disease (Dal-Bianco et al., 2021).

Microglia iron accumulation promotes the progression of Alzheimer's disease (AD) and Huntington's disease (HD). The clinical autopsy results of patients with AD showed that iron accumulation occurred in the microglia of the frontal cortex (van Duijn et al., 2017). Coculture of microglia with FAC resulted in microglia iron overload, establishing an in vitro model of aged microglia for culture with SH-SY5Y neurons and a subsequent increase in the level of Aβ in the medium (Angelova & Brown, 2018a). A later mechanistic study showed that microglia iron overload reduced the secretion of the insulin-degrading enzyme that degraded Aβ followed by extracellular Aβ accumulation-caused neurotoxicity (Angelova & Brown, 2018a). The activation of the kynurenine pathway (KP) for tryptophan degradation promoted the progress of HD. Indoleamine-2,3-dioxygenase (IDO) expressed in microglia was the key enzyme of the KP (Donley et al., 2021). After neonatal HD mice were supplemented with iron, microglia were activated and IDO activity was increased, thus activating KP pathway and promoting the progress of HD (Donley et al., 2021).

Microglia iron accumulation drove microglia transformation into the M1 phenotype and glycolysis phenotype. Microglia iron accumulation significantly increased TNF expression, and TNF drove the increase of microglia M1 phenotype and the decrease of M2 phenotype, which was detrimental to the recovery after spinal cord injury (Kroner et al., 2014). Microglia iron accumulation induced by ferric chloride increased the expression of TNF-α and IL-6 and drove microglia transformation into the glycolytic phenotype (Holland et al., 2018). The polarization of microglia to M1 phenotype is often accompanied by the transformation of cells to glycolytic phenotype (Orihuela et al., 2016).

Fe²⁺ in microglia activates reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX)2 in microglia. In a coculture of rat neurons and astrocytes with microglia and Fe²⁺ compared to that with Fe²⁺ only, the number of dopaminergic neurons were significantly lower, indicating that microglia plays a major role in Fe²⁺ induced neurotoxicity (Zhang et al., 2014). The Fe²⁺ in microglia activated NOX2, which increased the production of superoxide and ROS, thus promoting neuroinflammation and producing neurotoxicity (Zhang et al., 2014).

Inflammation and Microglia Iron Accumulation Jointly Promote Neuroinflammation

Microglia iron accumulation and inflammatory substances jointly aggravate the progression of neuroinflammation. After FAC induced microglia iron overload and subsequent LPS treatment, microglia were induced to release more IL-1β and TNF-α (Wang et al., 2013). Compared with that in LPS alone, the combined treatment of Fe²⁺ and LPS significantly increased the production of ROS in microglia (Yauger et al., 2019). Aβ binding to toll-like receptors (TLRs) on microglia activated the NF-κB pathway and subsequently led to an increased expression of IL-1β. Additionally, costimulation of microglia with iron and Aβ significantly increased the expression of IL-1β (Nnah et al., 2020). Microglia iron accumulation increased the expression of IL-6 mRNA (Zhou et al., 2017). IL-6 activated the JNK pathway to upregulate the expression of iron regulatory protein 1 and DMT1 while downregulating the expression of FPN1, which led to further microglia iron accumulation (Zhou et al., 2017).

The simultaneous occurrence of iron accumulation and neuroinflammation amplify the production of ROS and promote iron overload, resulting in neuronal death (Urrutia et al., 2021). Microglia iron accumulation and neuroinflammation also interact to lead to iron overload and a strong inflammatory reaction, which further aggravates the brain damage and its disorders.

Inhibition of Microglia Iron Accumulation Prevents Neuroinflammation

DMT1 inhibition, knockdown of DMT1 gene, and iron chelation significantly reduced the expression of IL-1β in microglia induced by Aβ and FAC (Nnah et al., 2020). Noggin, an antagonist of bone morphogenetic protein (BMP), blocked the BMP/Hepc pathway promoting the release of iron in microglia and improving the prognosis of cerebral ischemia injury (Shin et al., 2018). Deferoxamine (DFO) provided neuroprotection by enhancing the expression of HO-1 in microglia and chelating iron ions after subarachnoid hemorrhage (SAH) (LeBlanc et al., 2016). HO-1 decomposed heme to produce toxic Fe²⁺ and neuroprotective carbon monoxide (CO) in microglia (LeBlanc et al., 2016). Because DFO chelates Fe²⁺ and raises the content of CO, it provides neuroprotection by increasing the expression of HO-1 in microglia.

Fe²⁺ raises the production of ROS in microglia in a NOX-dependent manner. Exposure to Fe²⁺ and LPS raised the content of ROS in microglia, while inhibition of NOX2 and NOX4 significantly reduced the production of ROS (Yauger et al., 2019). The use of NOX2 inhibitor or NOX2 knockout mice reduced the production of superoxide and ROS in microglia induced by Fe²⁺, thereby reducing neurotoxicity (Zhang et al., 2014). Microglia iron accumulation activated NOX and then drove the progression of neuroinflammation. Therefore, inhibition of microglia iron accumulation could inhibit the progression of neuroinflammation. (Figure 1)

Figure 1.

Relationship between microglia iron accumulation and neuroinflammation. Iron accumulation promotes microglia transformation into M1 type, leading to an increased release of the proinflammatory factors IL- 1β, IL-6, and TNF-α. In addition, either IL- 1β, IL-6, or TNF-α induced microglia iron accumulation. Thus, microglia iron accumulation and inflammation promote each other, exacerbating the progression of neuroinflammation. interleukin (IL), tumor necrosis factor (TNF), nuclear factor-κB (NF-κB), c-Jun N-terminal kinase (JNK), Sanfilippo syndrome (SP), Parkinson's disease (PD), α-synuclein (α-syn), β-amyloid (Aβ), reactive oxygen species (ROS), multiple sclerosis (MS), Alzheimer's disease (AD), Huntington's disease (HD), reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX), toll-like receptors (TLRs).

Ferroptosis and its Regulation Mechanism

Ferroptosis is a type of iron-dependent cell death (Dixon et al., 2012); iron accumulation promotes phospholipid peroxidation and drives cell ferroptosis (Jiang et al., 2021; Stockwell et al., 2020). Ferroptosis is a form of cell death with morphological and immunological characteristics different to necroptosis, apoptosis, and autophagy (Xie et al., 2016). During the process of cell ferroptosis, the size of the nucleus is normal, and the chromatin does not agglutinate; mitochondria become significantly smaller, mitochondrial cristae decrease significantly or even disappear, mitochondrial membrane density increases, and mitochondrial outer membrane is ruptured (Stockwell et al., 2017; Xie et al., 2016). Cell ferroptosis is accompanied by the presence of iron, ROS, and polyunsaturated fatty acid-containing phospholipids (PUFA-PLs). Phospholipid peroxidation will destroy the cell membrane integrity, ultimately resulting in cell ferroptosis (Jiang et al., 2021).

Iron Metabolic Part of Cell Ferroptosis

Iron is an essential trace element required by the human body for normal life activities. It is also indispensable for the normal functioning of the brain. Iron takes part in oxygen transport, neurotransmitter synthesis, myelination, mitochondrial energy metabolism, cell division, and other processes (McCarthy et al., 2018; Urrutia et al., 2021). The main sources of iron in the body are iron released by erythrocyte degradation and iron absorbed in food (Brown et al., 2020). Iron exhibits redox activity and has two forms, ferrous (Fe²⁺) and ferric (Fe³⁺), which can be interconverted (Nnah & Wessling-Resnick, 2018).

The continuous accumulation of iron ions in cells triggers ferroptosis. There are four main sources of iron ions in the process of cell ferroptosis (Salvador, 2010): 1. After transferrin (Tf) receptor 1 on the cell membrane binds to Tf which is rich in Fe³⁺, the cell forms an endosome through endocytosis and Tf releases Fe³⁺ in the acidic environment of the endosome; subsequently, Fe³⁺ is transformed into Fe²⁺ which enters the cytoplasm; 2. Extracellular free Fe²⁺ is transported into the cell mediated by DMT1; 3. FRN which stores Fe³⁺ is degraded by autophagy mediated by nuclear receptor coactivator 4 (NCOA4); subsequently, Fe³⁺ is transformed into Fe²⁺ which is released into the cytoplasm (Hou et al., 2016); 4. The heme in cells is degraded by catalysis of HO-1, and the generated Fe²⁺ increases the content of iron ions in the cytoplasm. Free Fe²⁺ in the cytoplasm is transformed into Fe³⁺ by ceruloplasmin; then, Fe³⁺ is discharged from the cell to the outside through FPN1 (Xu et al., 2017). The increase of free Fe²⁺ in the cytoplasm forms a labile iron pool, which has a toxic effect on cells (Salvador, 2010). Free radical HO• is produced by the Fenton reaction (Fe²⁺ + H₂O₂ = Fe³⁺ + OH⁻ + HO•) and ROS is produced by mitochondria oxidizing the cell membrane, which then cause cell ferroptosis (Bu et al., 2021).

Phospholipid Peroxidation Part of Cell Ferroptosis

Catalyzed by acyl-CoA synthetase long-chain family member 4 (ACSL4), polyunsaturated fatty acids (PUFAs) and coenzyme A produce PUFA-CoA; subsequently, PUFA-CoA reacts with phosphatidylethanolamine through lysophosphatidylcholine acyltransferase 3 (LPCAT3) to produce PUFA-PLs (Jiang et al., 2021; Kagan et al., 2017). In response to the action of free radicals produced by the Fenton reaction or lipoxygenases (LOXs), PUFA-PLs are transformed into phospholipid hydroperoxides (PLOOHs) and the continuous accumulation of PLOOHs will cause irreversible damage to the cell membrane and ultimately cause cell death by destroying the function of the cell membrane (Jiang et al., 2021). LOXs which contribute to lipid peroxidation are deemed to be crucial for cell ferroptosis (Shah et al., 2018; Yang et al., 2016). Vitamin E prevents cell ferroptosis by inhibiting LOXs (Kagan et al., 2017).

The cystine/glutamate antiporter (System X_C⁻) is an antiporter for transporting amino acids, and the two peptide chains of the solute carrier family 7 member 11 (SLC7A11) and SLC3A2 interact to constitute System X_C⁻ (Bridges et al., 2012). In response to the action of System X_C⁻, intracellular glutamate is transported outside the cell while extracellular cystine is transferred into the cell (Jiang et al., 2021). After cystine receives a hydrogen proton in the cell, it is converted into cysteine which provides raw materials for the next step of glutathione (GSH) synthesis (Jiang et al., 2021). Glutathione peroxidase 4 (GPX4) action results in GSH changing PLOOHs to corresponding alcohols (PLOHs) (Jiang et al., 2021). Hence, in the presence of GPX4, GSH protects the cell membrane by reducing the accumulation of PLOOHs. Therefore, System X_C⁻-GPX4-GSH is extremely important to inhibit cell ferroptosis (Jiang et al., 2021). In addition, ferroptosis suppressor protein 1 (FSP1) increases ubiquinol and α-tocopherol content, inhibiting phospholipid peroxidation (Jiang et al., 2021). (Figure 2)

Figure 2.

Molecular regulatory mechanism of ferroptosis. Either Tf degradation, ferritinophagy, or heme degradation releases Fe²⁺. Extracellular free Fe²⁺ is transported into the cell mediated by DMT1. The increase of free Fe²⁺ in the cytoplasm forms a labile iron pool. Fe³⁺ is discharged from the cell to the outside through FPN1. Fe²⁺ in the cytoplasm significantly increases the production of HO• and ROS. PUFAs is converted to PUFA-PLs under the stepwise catalysis by ACSL4 and LPCAT3. Either HO•, ROS, or LOXs promotes PUFA-PLs transforming into PLOOHs. PLOOHs cause the phospholipid peroxidation of cell membrane, which leads to cell ferroptosis. GSH reduces PLOOHs content under the catalysis by GPX4, thereby inhibiting cell ferroptosis. Either microglia iron accumulation or phospholipid peroxidation increases the release of inflammatory cytokines, leading to neuroinflammation. ferroportin 1 (FPN1), divalent metal transporter 1 (DMT1), heme oxygenase-1 (HO-1), reactive oxygen species (ROS), reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX), polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), transferrin (Tf), acyl-CoA synthetase long-chain family member 4 (ACSL4), polyunsaturated fatty acids (PUFAs), lysophosphatidylcholine acyltransferase 3 (LPCAT3), lipoxygenases (LOXs), phospholipid hydroperoxides (PLOOHs), cystine/glutamate antiporter (System X_C⁻), glutathione (GSH), oxidized glutathione (GSSG), glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), dihydrobiopterin (BH2), tetrahydrobiopterin (BH4).

Microglia Ferroptosis may be a new Target for the Prevention and Treatment of Neuroinflammation

Cell Iron Accumulation Causes Cell Ferroptosis

After knockdown of neuronal FPN1, mitochondria in neurons exhibited signs of ferroptosis such as rupture and atrophy (Bao et al., 2021). Concurrently, iron content and the level of lipid peroxidation were increased, indicating that cell iron accumulation promoted cell ferroptosis (Bao et al., 2021). Erastin induced the increase of iron and ROS content in SH-SY5Y neurons and the decrease of cell viability (Geng et al., 2018). Upregulation of FPN1 expression significantly reduced iron content induced by Erastin in SH-SY5Y neurons and increased cell viability (Geng et al., 2018). Knockdown of FPN1 genes further promoted the ferroptosis process of SH-SY5Y neurons induced by Erastin, demonstrating that the iron accumulation in SH-SY5Y neurons drove the ferroptosis process (Geng et al., 2018). Ectopic endometrial stromal cells (EESCs) exhibited ferroptosis induced by Erastin, which decreased the content of FPN1 and led to iron accumulation (Li et al., 2021c). Further in vitro studies found that knockdown of FPN1 expression increased the level of lipid peroxidation and ROS content in EESCs induced by Erastin (Li et al., 2021c). However, overexpressed FPN1 inhibited the impact of Erastin-induced EESC ferroptosis, indicating that EESC iron accumulation significantly affected ferroptosis progression (Li et al., 2021c). Ubiquitin specific protease 35 (USP35) participates in cell proliferation. Knockdown of the USP35 gene resulted in lung cancer cell ferroptosis and overexpression of USP35 inhibited ferroptosis induced by Erastin/RSL3 (Tang et al., 2021). Further research found that knockdown of the expression of USP35 significantly reduced the expression level of FPN1 in lung cancer cells. These findings demonstrated that knockdown of USP35 expression induced cell ferroptosis, which may be achieved by reducing the content of FPN1 in lung cancer cells (Tang et al., 2021). Therefore, cell iron accumulation caused by reduced cell iron output promotes cell ferroptosis.

Erastin directly inhibits System X_C⁻ to cause the reduction of GSH production, thus promoting cell ferroptosis (Dixon et al., 2012). Erastin-induced cell ferroptosis in mouse embryonic fibroblasts or human fibrosarcoma cells with autophagy-related gene knockout significantly reduced intracellular Fe²⁺ content and cell death and inhibited lipid peroxidation compared to that in wild-type cells (Hou et al., 2016). Knockdown of the NCOA4 gene in human pancreatic cancer cells or human fibrosarcoma cells also significantly reduced cell death and intracellular Fe²⁺ content and inhibited lipid peroxidation after Erastin treatment (Hou et al., 2016). Knockout of autophagy-related genes in primary pulmonary fibroblasts (PPF) or treatment of PPF with an autophagy inhibitor inhibited cell death and reduced intracellular ROS and lipid peroxidation levels induced by Erastin (Park & Chung, 2019). These results demonstrate that ferritinophagy enhances cell ferroptosis and is a key step in cell ferroptosis.

After iron overload in primary cortical neurons treated with FAC, ROS accumulation and lipid peroxidation level were increased and the content of GPX4 were decreased in neurons, mitochondria shrunk significantly, while these were all improved after FAC-chelating DFO treatment (Feng et al., 2021). In vitro studies showed that bleomycin promoted iron accumulation, increased ROS content in the lung epithelial cell (MLE-12), and caused ferroptosis characteristics such as mitochondrial atrophy and increased membrane density (Cheng et al., 2021). DFO inhibited the action of bleomycin on MLE-12, indicating that MLE-12 iron accumulation led to cell ferroptosis (Cheng et al., 2021).

In conclusion, the iron accumulation in the cell triggers the process of cell ferroptosis, followed by accumulation of PLOOHs in the phospholipid peroxidation steps of ferroptosis, ultimately resulting in cell ferroptosis. After intraperitoneal LPS injection in aged mice, overexpression of HO-1 in microglia led to iron accumulation (Fernández-Mendívil et al., 2021). Moreover, overexpression of HO-1 in microglia increased the content of ROS and decreased the expression of GPX4 (Fernández-Mendívil et al., 2021). Thus, microglia iron accumulation also promotes the process of cell ferroptosis and causes the lethal accumulation of PLOOHs, which eventually leads to the ferroptosis of microglia.

The accumulation of iron in cells occurs in the initial steps of ferroptosis. Inhibiting microglia iron accumulation as described above prevent and treat neuroinflammation. This action may be due to the inhibition of iron accumulation in the process of microglia ferroptosis. Moreover, inhibiting microglia iron accumulation may decrease PLOOHs accumulation, thereby reducing the ferroptosis of microglia. The decrease of iron and PLOOHs significantly reduce the expression and release of inflammatory factors in microglia. Therefore, inhibition of microglia iron accumulation to prevent and treat neuroinflammation may be ultimately achieved by inhibiting the ferroptosis of microglia.

Inhibiting Microglia Phospholipid Peroxidation Prevents Neuroinflammation

Nitrogen-doped graphene quantum dots (N-GQDs) are a nanomaterial used widely in the fields of biomedicine and neuroscience. In vitro experimental studies found that N-GQDs treatment decreased the content of GSH, SLC7A11, and GPX4 in microglia and increased the content of Fe²⁺, ROS, and lipid peroxide, indicating that N-GQDs induced microglia ferroptosis. Simultaneously, N-GQDs upregulated the expression of proinflammatory factors IL-1β and TNF-α in microglia (Wu et al., 2022). Therefore, proinflammatory factors were released and caused neuroinflammation when microglia underwent ferroptosis (Wu et al., 2020, 2022).

Additionally, inhibiting phospholipid peroxidation in the process of microglia ferroptosis prevents neuroinflammation. ACSL4 is an enzyme that catalyzes PUFAs, which affect the sensitivity to cell ferroptosis. Knockdown of the ACSL4 gene in microglia decreased the sensitivity of microglia to ferroptosis and reduced the production of proinflammatory cytokines (Cui et al., 2021a). RSL3 resists lipid peroxidation by inhibiting the catalytic activity of GPX4, thereby promoting cell ferroptosis (Jiang et al., 2021). After treatment of microglia with RSL3, the mRNA expression of proinflammatory factor TNF-α, IL-6, and IL-1β were increased, revealing that the development of microglia ferroptosis is accompanied by an increased expression of inflammatory factors (Cui et al., 2021b).

Inhibition of phospholipid peroxidation during microglia ferroptosis alleviates the damage of intracerebral hemorrhage. Ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) capture unstable free radicals and exert an anti-lipid peroxidation effect，so they are efficient inhibitor of ferroptosis (Zilka et al., 2017). Fer-1 drove microglia transformation to the M2 phenotype and enhanced the phagocytosis of microglia, thereby reducing the inflammatory response after intracerebral hemorrhage (Huang et al., 2022). Lip-1 significantly decreased the number of microglia M1 phenotype after SAH (Cao et al., 2021). Additionally, the content of IL-6, IL-1β, and TNF-α was significantly reduced in the ipsilateral cortex (Cao et al., 2021). After SAH, mitochondria in microglia showed signs of ferroptosis such as increased mitochondrial atrophy and mitochondrial membrane density (Gao et al., 2022). However, cepharanthine (CEP) reduced the damage to microglia mitochondria after SAH, indicating that CEP inhibits microglia ferroptosis (Gao et al., 2022). Further study found that CEP reduced the lethal accumulation of PLOOHs by inhibiting the expression of 15-lipoxygenase-1, thereby inhibiting microglia ferroptosis which was conducive to the repair of nerve injury after SAH (Gao et al., 2022). SLC7A11 encodes for a light amino acid light chain in the System X_C⁻ (Bridges et al., 2012). The upregulation of SLC7A11 expression is beneficial to the synthesis of GSH which inhibits cell ferroptosis. Resveratrol increases the expression of SLC7A11 by activating the nuclear factor E2-related factor 2 (Nrf2) signal pathway to suppress rotenone-induced microglia ferroptosis (Li et al., 2021a). Thus, resveratrol plays an antioxidant and anti-inflammatory role.

The process of microglia ferroptosis is composed of two parts: microglia iron accumulation and phospholipid peroxidation. Neuroinflammation could be prevented by inhibiting iron accumulation or phospholipid peroxidation in the process of microglia ferroptosis. Therefore, inhibiting microglia ferroptosis could be a new target in the prevention and treatment of neuroinflammation. (Figure 3)

Figure 3.

Relationship between microglia ferroptosis and neuroinflammation. The process of microglia ferroptosis is composed of two parts: microglia iron accumulation and phospholipid peroxidation. Either inhibiting microglia iron accumulation or phosphololipid peroxidation restrains neuroinflammation. Therefore, inhibiting microglia ferroptosis is a novel target for the prevention and treatment of neuroinflammation. divalent metal transporter 1 (DMT1), interleukin (IL), β-amyloid (Aβ), ferric ammonium citrate (FAC), deferoxamine (DFO), reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX), reactive oxygen species (ROS), acyl-CoA synthetase long-chain family member 4 (ACSL4), ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), subarachnoid hemorrhage (SAH), solute carrier family 7 member 11 (SLC7A11), glutathione (GSH).

Summary and Outlook

Microglia iron accumulation is intertwined with neuroinflammation, and inflammation drives microglia iron accumulation. Microglia iron accumulation, almost involved in the occurrence of neuroinflammation, is accompanied by the polarization of microglia into the M1 phenotype and glycolysis phenotype, resulting in an increase of the expression and release of inflammatory factors. Hence, microglia iron accumulation and inflammation interact to jointly drive the development of neuroinflammation and aggravate CNS damage.

The iron accumulation and the phospholipid peroxidation part of the microglia ferroptosis process both activate microglia to release inflammatory cytokines and subsequently lead to neuroinflammation. Microglia iron accumulation triggers the process of microglia ferroptosis and could enhance the effect of phospholipids peroxidation. Inhibiting microglia iron accumulation could dampen neuroinflammation, which may be achieved by blocking iron accumulation in the process of microglia ferroptosis. In addition, a large amount of iron, free radicals, and cell debris from cells are released after microglia ferroptosis. Other resting microglia continue to remove these substances. As a result, more resting microglia are activated and further aggravate neuroinflammatory damage to tissues.

In conclusion, inhibiting microglia iron accumulation may be a new target for the prevention and treatment of neuroinflammation. Inhibiting microglia ferroptosis may also be a new target for the prevention and treatment of neuroinflammation. The relationship between microglia ferroptosis and neuroinflammation-related diseases needs further exploration. Using ferroptosis inhibitors Lip-1 and Fer-1 to investigate the relationship between microglia ferroptosis and neuroinflammation-related diseases could have great potential.

Footnotes

Acknowledgment

The authors are grateful to all members of the research group for their discussions. We would like to thank Editage () for English language editing.

Author Contribution

SHZ, SFL, and XG outlined the manuscript. SHZ and SFL wrote the manuscript. SHZ and SFL critically revised and approved the final version of the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (grant number 82060250), Guangxi Science and Technology Plan Project (grant number AD20238035), and Hunan Provincial Natural Science Foundation Project (grant number 2021JJ30614).

ORCID iDs

Shunfeng Liu

Shouhong Zhou

List of Abbreviations

References

Al Mamun

Chauhan

Ngwa

Sharmeen

Hazen

A. L.

Aronowski

J. A.

McCullough

L. D.

Liu

(2020). Microglial IRF5-IRF4 regulatory axis regulates neuroinflammation after cerebral ischemia and impacts stroke outcomes. Proceedings of the National Academy of Sciences of the United States of America, 117(3), 1742–1752. https://doi.org/10.1073/pnas.1914742117

Angelova

D. M.

Brown

D. R

. (2018a). Altered processing of β-amyloid in SH-SY5Y cells induced by model senescent microglia. ACS Chemical Neuroscience, 9(12), 3137–3152. https://doi.org/10.1021/acschemneuro.8b00334

Angelova

D. M.

Brown

D. R

. (2018b). Model senescent microglia induce disease related changes in α-synuclein expression and activity. Biomolecules, 8(3), 67. https://doi.org/10.3390/biom8030067

Bao

W. D.

Pang

Zhou

X. T.

Xiong

Chen

Wang

Xie

Y. Z.

Han

Z. T.

Zhang

H. H.

Wang

W. X.

Nelson

P. T.

Chen

J. G.

Man

H. Y.

Liu

Zhu

L. Q

. (2021). Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease. Cell Death and Differentiation, 28(5), 1548–1562. https://doi.org/10.1038/s41418-020-00685-9

Bridges

R. J.

Natale

N. R.

Patel

S. A

. (2012). System xc⁻ cystine/glutamate antiporter: An update on molecular pharmacology and roles within the CNS. British Journal of Pharmacology, 165(1), 20–34. https://doi.org/10.1111/j.1476-5381.2011.01480.x

Brown

R. A. M.

Richardson

K. L.

Kabir

T. D.

Trinder

Ganss

Leedman

P. J

. (2020). Altered iron metabolism and impact in cancer biology, metastasis, and immunology. Frontiers in Oncology, 10, 476. https://doi.org/10.3389/fonc.2020.00476

Z. Q.

H. Y.

Wang

Cui

Y. R.

Feng

J. C.

Feng

. (2021). Emerging role of ferroptosis in the pathogenesis of ischemic stroke: A new therapeutic target? ASN Neuro, 13, 17590914211037505. https://doi.org/10.1177/17590914211037505

Cao

Yan

J. R.

H. Z.

Zhuang

J. F.

Zhou

Peng

Y. C.

X. J.

X. Y.

Yao

Wei

Y. Y.

Tong

Zhou

Y. F.

Wang

. (2021). Selective ferroptosis inhibitor liproxstatin-1 attenuates neurological deficits and neuroinflammation after subarachnoid hemorrhage. Neuroscience Bulletin, 37(4), 535–549. https://doi.org/10.1007/s12264-020-00620-5

Cheng

Feng

Gao

Tang

Liu

Yue

Luo

. (2021). Iron deposition-induced ferroptosis in alveolar type II cells promotes the development of pulmonary fibrosis. Biochimica Et Biophysica Acta. Molecular Basis of Disease, 1867(12), 166204. https://doi.org/10.1016/j.bbadis.2021.166204

10.

Colonna

Butovsky

. (2017). Microglia function in the central nervous system during health and neurodegeneration. Annual Review of Immunology, 35, 441–468. https://doi.org/10.1146/annurev-immunol-051116-052358

11.

Cui

Zhang

Zhao

Shao

Liu

Sun

Zhang

. (2021a). ACSL4 Exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain, Behavior, and Immunity, 93, 312–321. https://doi.org/10.1016/j.bbi.2021.01.003

12.

Cui

Zhang

Zhou

Zhao

Kong

Ren

Yao

Wen

Guo

Gao

Sun

Wan

. (2021b). Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression. Journal of Neuroinflammation, 18(1), 249. https://doi.org/10.1186/s12974-021-02231-x

13.

Dal-Bianco

Grabner

Kronnerwetter

Weber

Höftberger

Berger

Auff

Leutmezer

Trattnig

Lassmann

Bagnato

Hametner

. (2017). Slow expansion of multiple sclerosis iron rim lesions: Pathology and 7T magnetic resonance imaging. Acta Neuropathologica, 133(1), 25–42. https://doi.org/10.1007/s00401-016-1636-z

14.

Dal-Bianco

Grabner

Kronnerwetter

Weber

Kornek

Kasprian

Berger

Leutmezer

Rommer

P. S.

Trattnig

Lassmann

Hametner

. (2021). Long-term evolution of multiple sclerosis iron rim lesions in 7T MRI. Brain: A Journal of Neurology, 144(3), 833–847. https://doi.org/10.1093/brain/awaa436

15.

Dixon

S. J.

Lemberg

K. M.

Lamprecht

M. R.

Skouta

Zaitsev

E. M.

Gleason

C. E.

Patel

D. N.

Bauer

A. J.

Cantley

A. M.

Yang

W. S.

Morrison

3rd Stockwell

B. R.

(2012). Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 149(5), 1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

16.

Donley

D. W.

Realing

Gigley

J. P.

Fox

J. H

. (2021). Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of huntington’s disease. PLoS One, 16(5), e0250606. https://doi.org/10.1371/journal.pone.0250606

17.

Feng

Min

Chen

Deng

Tan

Liu

Hou

. (2021). Iron overload in the motor cortex induces neuronal ferroptosis following spinal cord injury. Redox Biology, 43, 101984. https://doi.org/10.1016/j.redox.2021.101984

18.

Fernández-Mendívil

Luengo

Trigo-Alonso

García-Magro

Negredo

López

M. G

. (2021). Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism. Redox Biology, 38, 101789. https://doi.org/10.1016/j.redox.2020.101789

19.

Gao

Zhou

Fang

Pan

Wang

Zhang

Shao

. (2022). Cepharanthine attenuates early brain injury after subarachnoid hemorrhage in mice via inhibiting 15-lipoxygenase-1-mediated microglia and endothelial cell ferroptosis. Oxidative Medicine and Cellular Longevity, 2022, 4295208. https://doi.org/10.1155/2022/4295208

20.

Geng

Shi

B. J.

S. L.

Zhong

Z. Y.

Y. C.

Xua

W. L.

Zhou

Cai

J. H

. (2018). Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells. European Review for Medical and Pharmacological Sciences, 22(12), 3826–3836. https://doi.org/10.26355/eurrev_201806_15267

21.

Gillen

K. M.

Mubarak

Nguyen

T. D.

Pitt

. (2018). Significance and in vivo detection of iron-laden microglia in white matter multiple sclerosis lesions. Frontiers in Immunology, 9, 255. https://doi.org/10.3389/fimmu.2018.00255

22.

Guo

J. J.

Yue

Song

D. Y.

Bousset

Liang

Tang

Yuan

Melki

Tang

Chan

Guo

J. Y

. (2021). Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of macaca fascicularis. Cell Death & Disease, 12(1), 81. https://doi.org/10.1038/s41419-020-03369-x

23.

Holland

McIntosh

A. L.

Finucane

O. M.

Mela

Rubio-Araiz

Timmons

McCarthy

S. A.

Gun’ko

Y. K.

Lynch

M. A

. (2018). Inflammatory microglia are glycolytic and iron retentive and typify the microglia in APP/PS1 mice. Brain, Behavior, and Immunity, 68, 183–196. https://doi.org/10.1016/j.bbi.2017.10.017

24.

Hou

Xie

Song

Sun

Lotze

M. T.

Zeh

H. J

3rd Kang

Tang

(2016). Autophagy promotes ferroptosis by degradation of ferritin. Autophagy, 12(8), 1425–1428. https://doi.org/10.1080/15548627.2016.1187366

25.

Huang

Zhang

Zhao

Chen

. (2022). Ferrostatin-1 polarizes microglial cells toward M2 phenotype to alleviate inflammation after intracerebral hemorrhage. Neurocritical Care, 36(3), 942–954. https://doi.org/10.1007/s12028-021-01401-2

26.

Jiang

Stockwell

B. R.

Conrad

. (2021). Ferroptosis: Mechanisms, biology and role in disease. Nature Reviews. Molecular Cell Biology, 22(4), 266–282. https://doi.org/10.1038/s41580-020-00324-8

27.

Kagan

V. E.

Mao

Angeli

J. P.

Doll

Croix

C. S.

Dar

H. H.

Liu

Tyurin

V. A.

Ritov

V. B.

Kapralov

A. A.

Amoscato

A. A.

Jiang

Anthonymuthu

Mohammadyani

Yang

Proneth

Klein-Seetharaman

Watkins

Bahar

Greenberger

Mallampalli

R. K.

Stockwell

B. R.

Tyurina

Y. Y.

Conrad

Bayır

. (2017). Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nature Chemical Biology, 13(1), 81–90. https://doi.org/10.1038/nchembio.2238

28.

C. J.

Gao

S. L.

Lin

T. K.

Chu

P. Y.

Lin

H. Y

. (2021). Ferroptosis as a major factor and therapeutic target for neuroinflammation in Parkinson’s disease. Biomedicines, 9(11), 1679. https://doi.org/10.3390/biomedicines9111679

29.

Kroner

Greenhalgh

A. D.

Zarruk

J. G.

Passos Dos Santos

Gaestel

David

(2014). TNF And increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron, 83(5), 1098–1116. https://doi.org/10.1016/j.neuron.2014.07.027

30.

LeBlanc

R. H.

3rd Chen

Selim

M. H.

Hanafy

K. A.

(2016). Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine. Journal of Neuroinflammation, 13(1), 244. https://doi.org/10.1186/s12974-016-0709-1

31.

Leng

Edison

. (2021). Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here? Nature Reviews Neurology, 17(3), 157–172. https://doi.org/10.1038/s41582-020-00435-y

32.

Lan

Han

Durham

Wan

Weiland

Koehler

R. C.

Wang

. (2021b). Microglia-derived interleukin-10 accelerates post-intracerebral hemorrhage hematoma clearance by regulating CD36. Brain, Behavior, and Immunity, 94, 437–457. https://doi.org/10.1016/j.bbi.2021.02.001

33.

Shen

Xiao

Sun

. (2021a). Resveratrol attenuates rotenone-induced inflammation and oxidative stress via STAT1 and Nrf2/Keap1/SLC7A11 pathway in a microglia cell line. Pathology, Research and Practice, 225, 153576. https://doi.org/10.1016/j.prp.2021.153576

34.

Zeng

Yin

Shan

Gao

. (2021c). Erastin induces ferroptosis via ferroportin-mediated iron accumulation in endometriosis. Human Reproduction, 36(4), 951–964. https://doi.org/10.1093/humrep/deaa363

35.

Maccioni

R. B.

González

Andrade

Cortés

Tapia

J. P.

Guzmán-Martínez

. (2018). Alzheimer's disease in the perspective of neuroimmunology. The Open Neurology Journal, 12, 50–56. https://doi.org/10.2174/1874205X01812010050

36.

Martin-Bastida

Tilley

B. S.

Bansal

Gentleman

S. M.

Dexter

D. T.

Ward

R. J

. (2021). Iron and inflammation: In vivo and post-mortem studies in Parkinson’s disease. Journal of Neural Transmission, 128(1), 15–25. https://doi.org/10.1007/s00702-020-02271-2

37.

McCarthy

R. C.

Sosa

J. C.

Gardeck

A. M.

Baez

A. S.

Lee

C. H.

Wessling-Resnick

. (2018). Inflammation-induced iron transport and metabolism by brain microglia. The Journal of Biological Chemistry, 293(20), 7853–7863. https://doi.org/10.1074/jbc.RA118.001949

38.

McIntosh

Mela

Harty

Minogue

A. M.

Costello

D. A.

Kerskens

Lynch

M. A

. (2019). Iron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice. Brain Pathology, 29(5), 606–621. https://doi.org/10.1111/bpa.12704

39.

Mehta

Pei

Yang

Swamy

Boster

Schmalbrock

Pitt

. (2013). Iron is a sensitive biomarker for inflammation in multiple sclerosis lesions. PLoS One, 8(3), e57573. https://doi.org/10.1371/journal.pone.0057573

40.

Nayak

Roth

T. L.

McGavern

D. B

. (2014). Microglia development and function. Annual Review of Immunology, 32, 367–402. https://doi.org/10.1146/annurev-immunol-032713-120240

41.

Nnah

I. C.

Lee

C. H.

Wessling-Resnick

. (2020). Iron potentiates microglial interleukin-1β secretion induced by amyloid-β. Journal of Neurochemistry, 154(2), 177–189. https://doi.org/10.1111/jnc.14906

42.

Nnah

I. C.

Wessling-Resnick

. (2018). Brain iron homeostasis: A focus on microglial iron. Pharmaceuticals, 11(4), 129. https://doi.org/10.3390/ph11040129

43.

Olmedo-Díaz

Estévez-Silva

Orädd

Af Bjerkén

Marcellino

Virel

. (2017). An altered blood-brain barrier contributes to brain iron accumulation and neuroinflammation in the 6-OHDA rat model of Parkinson’s disease. Neuroscience, 362, 141–151. https://doi.org/10.1016/j.neuroscience.2017.08.023

44.

Orihuela

McPherson

C. A.

Harry

G. J

. (2016). Microglial M1/M2 polarization and metabolic states. British Journal of Pharmacology, 173(4), 649–665. https://doi.org/10.1111/bph.13139

45.

Park

Chung

S. W

. (2019). ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation. Cell Death & Disease, 10(11), 822. https://doi.org/10.1038/s41419-019-2064-5

46.

Puy

Darwiche

Trudel

Gomila

Lony

Puy

Lefebvre

Vitry

Boullier

Karim

Ausseil

. (2018). Predominant role of microglia in brain iron retention in sanfilippo syndrome, a pediatric neurodegenerative disease. Glia, 66(8), 1709–1723. https://doi.org/10.1002/glia.23335

47.

Rathore

K. I.

Redensek

David

. (2012). Iron homeostasis in astrocytes and microglia is differentially regulated by TNF-α and TGF-β1. Glia, 60(5), 738–750. https://doi.org/10.1002/glia.22303

48.

Rodríguez

A. M.

Rodríguez

Giambartolomei

G. H

. (2022). Microglia at the crossroads of pathogen-induced neuroinflammation. ASN Neuro, 14, 17590914221104566. https://doi.org/10.1177/17590914221104566

49.

Russo

M. V.

McGavern

D. B

. (2016). Inflammatory neuroprotection following traumatic brain injury. Science (New York, N.Y.), 353(6301), 783–785. https://doi.org/10.1126/science.aaf6260

50.

Salvador

G. A

. (2010). Iron in neuronal function and dysfunction. Biofactors, 36(2), 103–110. https://doi.org/10.1002/biof.80

51.

Shah

Shchepinov

M. S.

Pratt

D. A

. (2018). Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Central Science, 4(3), 387–396. https://doi.org/10.1021/acscentsci.7b00589

52.

Shin

J. A.

Kim

Y. A.

Kim

H. W.

Kim

H. S.

Lee

K. E.

Kang

J. L.

Park

E. M

. (2018). Iron released from reactive microglia by noggin improves myelin repair in the ischemic brain. Neuropharmacology, 133, 202–215. https://doi.org/10.1016/j.neuropharm.2018.01.038

53.

Stephenson

Nutma

van der Valk

Amor

. (2018). Inflammation in CNS neurodegenerative diseases. Immunology, 154(2), 204–219. https://doi.org/10.1111/imm.12922

54.

Stockwell

B. R.

Friedmann Angeli

J. P.

Bayir

Bush

A. I.

Conrad

Dixon

S. J.

Fulda

Gascón

Hatzios

S. K.

Kagan

V. E.

Noel

Jiang

Linkermann

Murphy

M. E.

Overholtzer

Oyagi

Pagnussat

G. C.

Park

Ran

Rosenfeld

C. S.

Salnikow

Tang

Torti

F. M.

Torti

S. V.

Toyokuni

Woerpel

K. A.

Zhang

D. D

. (2017). Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 171(2), 273–285. https://doi.org/10.1016/j.cell.2017.09.021

55.

Stockwell

B. R.

Jiang

. (2020). Emerging mechanisms and disease relevance of ferroptosis. Trends in Cell Biology, 30(6), 478–490. https://doi.org/10.1016/j.tcb.2020.02.009

56.

Subhramanyam

C. S.

Wang

Dheen

S. T

. (2019). Microglia-mediated neuroinflammation in neurodegenerative diseases. Seminars in Cell & Developmental Biology, 94, 112–120. https://doi.org/10.1016/j.semcdb.2019.05.004

57.

Tang

Jiang

Mao

Zhao

Chen

Cheng

. (2021). Deubiquitinase USP35 modulates ferroptosis in lung cancer via targeting ferroportin. Clinical and Translational Medicine, 11(4), e390. https://doi.org/10.1002/ctm2.390

58.

Thomsen

M. S.

Andersen

M. V.

Christoffersen

P. R.

Jensen

M. D.

Lichota

Moos

. (2015). Neurodegeneration with inflammation is accompanied by accumulation of iron and ferritin in microglia and neurons. Neurobiology of Disease, 81, 108–118. https://doi.org/10.1016/j.nbd.2015.03.013

59.

Urrutia

Aguirre

Esparza

Tapia

Mena

N. P.

Arredondo

González-Billault

Núñez

M. T

. (2013). Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells. Journal of Neurochemistry, 126(4), 541–549. https://doi.org/10.1111/jnc.12244

60.

Urrutia

P. J.

Bórquez

D. A.

Núñez

M. T

. (2021). Inflaming the brain with iron. Antioxidants, 10(1), 61. https://doi.org/10.3390/antiox10010061

61.

van Duijn

Bulk

van Duinen

S. G.

Nabuurs

R. J. A.

van Buchem

M. A.

van der Weerd

Natté

. (2017). Cortical iron reflects severity of Alzheimer’s disease. Journal of Alzheimer’s Disease: JAD, 60(4), 1533–1545. https://doi.org/10.3233/jad-161143

62.

Wang

Song

Jiang

Wang

Xie

. (2013). Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons. Biochimica Et Biophysica Acta, 1832(5), 618–625. https://doi.org/10.1016/j.bbadis.2013.01.021

63.

Liang

Liu

Wang

Kong

Tang

. (2020). Induction of ferroptosis in response to graphene quantum dots through mitochondrial oxidative stress in microglia. Particle and Fibre Toxicology, 17(1), 30. https://doi.org/10.1186/s12989-020-00363-1

64.

Wang

Cheng

Liang

Chen

Kong

Tang

. (2022). Nitrogen-doped graphene quantum dots induce ferroptosis through disrupting calcium homeostasis in microglia. Particle and Fibre Toxicology, 19(1), 22. https://doi.org/10.1186/s12989-022-00464-z

65.

Xie

Hou

Song

Huang

Sun

Kang

Tang

. (2016). Ferroptosis: Process and function. Cell Death and Differentiation, 23(3), 369–379. https://doi.org/10.1038/cdd.2015.158

66.

Xiong

X. Y.

Liu

Yang

Q. W

. (2016). Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Progress in Neurobiology, 142, 23–44. https://doi.org/10.1016/j.pneurobio.2016.05.001

67.

Meng

Zhang

Wang

Xie

Wang

. (2022). 6-Hydroxydopamine Induces abnormal iron sequestration in BV2 microglia by activating iron regulatory protein 1 and inhibiting hepcidin release. Biomolecules, 12(2), 266. https://doi.org/10.3390/biom12020266

68.

Wang

Song

Wang

Jiang

Xie

. (2017). New progress on the role of glia in iron metabolism and iron-induced degeneration of dopamine neurons in Parkinson’s disease. Frontiers in Molecular Neuroscience, 10, 455. https://doi.org/10.3389/fnmol.2017.00455

69.

Wang

Zhang

Yan

Jia

. (2020). Polysaccharide from Schisandra chinensis acts via LRP-1 to reverse microglia activation through suppression of the NF-κB and MAPK signaling. Journal of Ethnopharmacology, 256, 112798. https://doi.org/10.1016/j.jep.2020.112798

70.

Zhang

Liu

Xie

Shi

Chen

Guo

Sun

Hong

Liu

. (2019). Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke. Cell Death & Disease, 10(8), 555. https://doi.org/10.1038/s41419-019-1777-9

71.

Yang

W. S.

Kim

K. J.

Gaschler

M. M.

Patel

Shchepinov

M. S.

Stockwell

B. R.

(2016). Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proceedings of the National Academy of Sciences of the United States of America, 113(34), E4966–E4975. https://doi.org/10.1073/pnas.1603244113

72.

Yauger

Y. J.

Bermudez

Moritz

K. E.

Glaser

Stoica

Byrnes

K. R

. (2019). Iron accentuated reactive oxygen species release by NADPH oxidase in activated microglia contributes to oxidative stress in vitro. Journal of Neuroinflammation, 16(1), 41. https://doi.org/10.1186/s12974-019-1430-7

73.

Zhang

Yan

Z. F.

Gao

J. H.

Sun

Huang

X. Y.

Liu

S. Y.

Cao

C. J.

Zuo

L. J.

Chen

Z. J.

Wang

Hong

J. S.

Wang

X. M

. (2014). Role and mechanism of microglial activation in iron-induced selective and progressive dopaminergic neurodegeneration. Molecular Neurobiology, 49(3), 1153–1165. https://doi.org/10.1007/s12035-013-8586-4

74.

Zhou

Xie

Wang

. (2017). Interleukin-6 regulates iron-related proteins through c-jun N-terminal kinase activation in BV2 microglial cell lines. PLoS One, 12(7), e0180464. https://doi.org/10.1371/journal.pone.0180464

75.

Zilka

Shah

Friedmann Angeli

J. P.

Griesser

Conrad

Pratt

D. A

. (2017). On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death. ACS Central Science, 3(3), 232–243. https://doi.org/10.1021/acscentsci.7b00028

New Target for Prevention and Treatment of Neuroinflammation: Microglia Iron Accumulation and Ferroptosis

Abstract

Keywords

Introduction

Microglia and Neuroinflammation

Neuroinflammation and Microglia Iron Accumulation

Neuroinflammation Induces Microglia Iron Accumulation

Microglia Iron Accumulation Leads to Neuroinflammation

Inflammation and Microglia Iron Accumulation Jointly Promote Neuroinflammation

Inhibition of Microglia Iron Accumulation Prevents Neuroinflammation

Ferroptosis and its Regulation Mechanism

Iron Metabolic Part of Cell Ferroptosis

Phospholipid Peroxidation Part of Cell Ferroptosis

Microglia Ferroptosis may be a new Target for the Prevention and Treatment of Neuroinflammation

Cell Iron Accumulation Causes Cell Ferroptosis

Inhibiting Microglia Phospholipid Peroxidation Prevents Neuroinflammation

Summary and Outlook

Footnotes

Acknowledgment

Author Contribution

Declaration of Conflicting Interests

Funding

ORCID iDs

List of Abbreviations

References