The Interplay between Intracellular Iron Homeostasis and Neuroinflammation in Neurodegenerative Diseases

Abstract

Iron is essential for life. Many enzymes require iron for appropriate function. However, dysregulation of intracellular iron homeostasis produces excessive reactive oxygen species (ROS) via the Fenton reaction and causes devastating effects on cells, leading to ferroptosis, an iron-dependent cell death. In order to protect against harmful effects, the intracellular system regulates cellular iron levels through iron regulatory mechanisms, including hepcidin-ferroportin, divalent metal transporter 1 (DMT1)-transferrin, and ferritin-nuclear receptor coactivator 4 (NCOA4). During iron deficiency, DMT1-transferrin and ferritin-NCOA4 systems increase intracellular iron levels via endosomes and ferritinophagy, respectively. In contrast, repleting extracellular iron promotes cellular iron absorption through the hepcidin-ferroportin axis. These processes are regulated by the iron-regulatory protein (IRP)/iron-responsive element (IRE) system and nuclear factor erythroid 2-related factor 2 (Nrf2). Meanwhile, excessive ROS also promotes neuroinflammation by activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB forms inflammasomes, inhibits silent information regulator 2-related enzyme 1 (SIRT1), and induces pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β). Furthermore, 4-hydroxy-2,3-trans-nonenal (4-HNE), the end-product of ferroptosis, promotes the inflammatory response by producing amyloid-beta (Aβ) fibrils and neurofibrillary tangles in Alzheimer's disease, and alpha-synuclein aggregation in Parkinson's disease. This interplay shows that intracellular iron homeostasis is vital to maintain inflammatory homeostasis. Here, we review the role of iron homeostasis in inflammation based on recent findings.

Keywords: 4-HNE; NF-κB; Nrf2; ferroptosis; intracellular iron homeostasis; neurodegenerative diseases; neuroinflammation.

Figure 1

The IRP/IRE system. IRPs consist of two proteins, IRP1 and IRP2. Under iron-rich conditions, iron forms iron–sulfur clusters. Iron–sulfur clusters bind to IRP1. IRP1 acts as c-aconitase. Additionally, iron–sulfur clusters bind to FBXL5 (not described) and mediate IRP2 ubiquitination-dependent degradation. Eventually, inhibition of IRPs leads to the degradation of iron uptake-related mRNAs by the endonuclease. By contrast, under iron shortage conditions, IRPs bind to the IRE within mRNA. This stabilizes the mRNAs or prevents their translation in the nucleus. DMT1, divalent metal transporter 1; FPN1, ferroportin 1; FTH1, ferritin heavy chain; FTL, ferritin light chain; IRE, iron-responsive element; IRP, iron-regulatory protein; IRP1, iron-regulatory protein 1; IRP2, iron-regulatory protein 2; Tfr, transferrin receptor.

Figure 2

Cellular iron regulation in ferritinophagy. Fe³⁺ is reduced to Fe²⁺ via Dcytb, and Fe²⁺ is then transported into cells via Tf–Tfr or DMT1. Oxidized Fe³⁺ is encapsulated by vesicles called endosomes. Next, Steap3 in the vesicles reduces Fe³⁺ to Fe²⁺ and releases it into the cytoplasm. Fe²⁺ binds to PCBP1 or PCBP2 and is delivered to FTH1, the mitochondria, or FPN1. FTH1 interacts with NCOA4 to store iron. Meanwhile, the interaction between hepcidin and FPN1 blocks the leakage of intracellular iron. When iron is deficient, the FTH1–NCOA4 complex releases iron through ferritinophagy. When iron is repleted, FPN1 exports iron into the extracellular space. In the extracellular space, Fe²⁺ is oxidized to Fe³⁺ by HEPH. Intracellular iron responds to H₂O₂ and produces ^•OH. ROS damages organelles. A white circle with numbers means iron movement by endocytosis. A yellow circle with numbers shows iron movement through a channel. DMT1, divalent metal transporter 1; DcytB, duodenal cytochrome B; Fe²⁺, ferrous iron; Fe³⁺, ferric iron; FTH1, ferritin heavy chain; FTL, ferritin light chain; FPN1, ferroportin 1; GSH, glutathione; HEPH, hephaestin; HERC2, HECT domain and RCC1-like domain 2; ^•OH, hydroxyl radical; H₂O₂, hydrogen peroxide; LC3, microtubule-associated protein 1A/1B-light chain 3; LIP, labile iron pool; NCOA4, nuclear receptor coactivator 4; PCBP1, poly(rC)-binding protein 1; PCBP2, poly(rC)-binding protein 2; ROS, reactive oxygen species; Steap3, six-transmembrane epithelial antigen of prostate family member 3; Tf, transferrin; TfR, transferrin receptor.

Figure 3

The regulation of cellular redox balance and inflammation. In redox regulation, ROS produced by IL-6 or the Fenton reaction promotes the dissociation of Nrf2 from Keap1 and activates Nrf2. Activated Nrf2 is translocated to the nucleus and initiates the transcription of antioxidant enzymes and proteins requiring iron. This process protects cells from ROS. During inflammation, ROS, DAMPs, or LPS activate NF-κB signal transduction by eliminating IκB-α via ubiquitination. NF-κB moves to the nucleus and induces the transcription of pro-inflammatory cytokines. In this process, inflammasomes are activated, and inflammation is increased. To prevent excessive inflammation, the Nrf2 pathway is activated, which suppresses inflammation-related proteins, such as inflammasomes, MIP2, MCP1, and the NF-κB pathway. Additionally, SIRT1 acts as a regulator and inhibits the activation of NF-κB. NF-κB also regulates the activation of the uncontrolled redox system by inhibiting Nrf2 activation. ARE, antioxidant response element; ATP, adenosine triphosphate; DAMP, damage-associated molecular pattern; FPN1, ferroportin 1; FTH1, ferritin heavy chain; ^•OH, hydroxyl radical; H₂O₂, hydrogen peroxide; IκB-α, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; IKKα, IκB kinase alpha; IL-1β, interleukin-1β; IL-6, interleukin-6; KEAP1, Kelch-like ECH-associated protein 1; LPS, lipopolysaccharide; MCP1, monocyte chemoattractant protein 1; MIP2, macrophage inflammatory protein 2; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-kappa B; Nrf2, nuclear factor erythroid 2-related factor 2; P, phosphorylation; PCBP2, poly(rC)-binding protein 2; PIR, pirin; ROS, reactive oxygen species; SIRT1, silent information regulator factor 2-related enzyme 1; STAT3, signal transducer and activator of transcription 3; TLR2, Toll-like receptor 2; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor-alpha; Ub, ubiquitin.

Figure 4

The interplay between iron homeostasis and inflammation in AD and PD. Increased cellular iron accelerates ^•OH production via the Fenton reaction. Excessive ^•OH increases lipid peroxidation, producing 4-HNE and activating COX2. 4-HNE promotes α-syn aggregation and continuously generates NFTs. These products are released to the extracellular space with the vesicles or activate the inflammatory response in cells. Additionally, 4-HNE can induce mitochondrial dysfunction by conjugating with mitochondrial proteins, causing electron leakage and enhancing ROS production. Ultimately, this response leads to the activation of the Nrf2-mediated antioxidant response. ROS can stimulate p53. p53 inhibits the NK-κB pathway and reduces ROS. However, there is still controversy about whether p53 prevents ferroptosis. COX2 is a pro-inflammatory enzyme. In addition, iron-binding to Aβ_1-40/42 fibrils drastically promotes the production of ROS. This damages the mitochondria and boosts ROS production. Ultimately, this cascade leads to the NF-κB-mediated inflammatory response and inflammasome formation. Meanwhile, NQO1 facilitates SIRT1 activation by providing more NAD⁺. SIRT1 promotes mitochondrial biogenesis by activating PGC1-α. Interaction between Aβ_1-40/42 and Zn²⁺ increases cellular iron content by blocking FPN. α-syn, alpha-synuclein; Aβ, amyloid β; AD, Alzheimer’s disease; APP, amyloid precursor protein; ARE, antioxidant response element; ATP, adenosine triphosphate; COX2, cyclooxygenase 2; DMT1, divalent metal transporter 1; e⁻, electron; Fe²⁺, ferrous iron; Fe³⁺, ferric iron; FPN1, ferroportin 1; FTH1, ferritin heavy chain; 4-HNE, hydroxy-2,3-trans-nonenal; H₂O₂, hydrogen peroxide; ^•OH, hydroxyl radical; IL-1β, interleukin-1β; IL-6, interleukin-6; LIP, labile iron pool; NAD⁺, nicotinamide adenine dinucleotide; NQO1, NAD(P)H quinone dehydrogenase 1; NF-κB, nuclear factor-κB; NFT, neurofibrillary tangle; Nrf2, nuclear factor erythroid 2-related factor 2; p53, tumor protein P53; PD, Parkinson’s disease; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PIR, pirin; PGs, prostaglandins; ROS, reactive oxygen species; SIRT1, silent information regulator factor 2-related enzyme 1; Tf, transferrin; Tfr, transferrin receptor; TNF-α, tumor necrosis factor-alpha; Zn²⁺, zinc ion.