The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

In the paper

“Under BH4 deficiency, T cells show dysfunctional ETC, enhanced ROS, and reduced ATP production in activated T cells.”

In the paper

“Under conditions of BH4 deficiency, as in our Gch1-ablated T cells, cytochrome-C reduction is compromised, resulting in dysfunctional mitochondrial respiration, increased superoxide formation and, ultimately diminished ATP production, all of which we observed (Cronin et al., 2018).”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“Using multiple T cell specific ablation strategies, we demonstrated that genetic inactivation of GCH1 or pharmacological inhibition of the terminal enzyme in the biosynthetic pathway of BH4, sepiapterin reductase (SPR), results in severely impaired proliferation of T cells (Cronin et al., 2018).”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“However, interestingly, T cell development or homeostasis as well as B cell and regulatory T cell (Treg) functions are unaffected by inhibition of this pathway.”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“Moreover, the T cells show dysregulated Mitoferrin, Frataxin, HO-1, Ferritin and overall reduced iron levels in the cell”

In the paper

“BH4 can not only act as a superoxide ROS scavenger but also directly reduce Fe3+ to Fe2+ and therefore affect cytochrome C (cyto-C) activity in the ETC.”

In the paper

“In genetic inactivation models, we did not detect any differences in iNOS expression or NO production in T cells, nor any detectable signs of activated T cells producing biogenic amine neurotransmitters that require co-factor BH4.”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“In orthotopic cancer transfer models, BH4-overproducing T cells have increased anti-cancer immunity, resulting in greatly reduced cancer burden (Cronin et al., 2018).”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“To this end, we developed a novel BH4 inhibitor, QM385, which targets SPR, and blocks both mouse and human T cell proliferation at nanomolar potency with good oral bioavailability and no observable side-effects at immune suppressant exposures (Cronin et al., 2018).”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“In such activated T cells, BH4 regulates both the reduction of Fe3+ and increases the availability of Fe2+ in the cell, which aid activated T cells in coordinating the increased metabolic needs for effector functions.”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“To this end, we developed a novel BH4 inhibitor, QM385, which targets SPR, and blocks both mouse and human T cell proliferation at nanomolar potency with good oral bioavailability and no observable side-effects at immune suppressant exposures (Cronin et al., 2018).”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“We also showed that by enhancing BH4 genetically, or pharmacologically with BH4 itself, T cells displayed heightened proliferation and, importantly, increased anti-tumor activity (Cronin et al., 2018).”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“To this end, we developed a novel BH4 inhibitor, QM385, which targets SPR, and blocks both mouse and human T cell proliferation at nanomolar potency with good oral bioavailability and no observable side-effects at immune suppressant exposures (Cronin et al., 2018).”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“Transferrin (Tf) is a glycoprotein containing two high affinity binding sites for ferric iron (Fe3+) (Aisen et al., 1978), which captures Fe3+ in the circulation (Figure 1).”

What the sources say

• Not checked yetcites Aisen et al., 1978 source

In the paper

“Iron deficiency is the most common pathology of iron homeostasis, eventually resulting in iron deficiency anemia, the most frequent anemia worldwide (Camaschella, 2015).”

What the sources say

• Not checked yetcites Camaschella, 2015 source

In the paper

“Ferric iron in the circulation is then bound by transferrin (Tf) and carried to cells and tissues (Muckenthaler et al., 2017).”

What the sources say

• Not checked yetcites Muckenthaler et al., 2017 source

In the paper

“This diferric Tf conjugate (Tf-Fe3+) not only prevents free, non-transferrin bound iron (NTBI), from engaging in Fenton chemistry to produce dangerous hydroxyl radicals, but also deprives invading pathogens of free iron to block their expansion and proliferation (Barber and Elde, 2014).”

What the sources say

• Not checked yetcites Barber and Elde, 2014 source

In the paper

“Accordingly, iron trafficking is controlled by cytokines and acute phase proteins, whereas the metal itself promotes lymphocyte and macrophage differentiation, anti-microbial immune effector function, and immune cell metabolism, as we will discuss later (Ganz and Nemeth, 2015; Soares and Weiss, 2015).”

What the sources say

• Not checked yetcites Ganz and Nemeth, 2015 source
• Not checked yetcites Soares and Weiss, 2015 source

In the paper

“The freed ferric iron is then reduced to its bio-active ferrous form, Fe2+ by the ferrireductase STEAP3 (six-transmembrane epithelial antigen of prostate 3) and shuttled into the cytosol from the endosome by DMT1 (Fleming et al., 1997; Gunshin et al., 1997; Ohgami et al., 2005; Figure 1).”

What the sources say

• Not checked yetcites Fleming et al., 1997 source
• Not checked yetcites Gunshin et al., 1997 source
• Not checked yetcites Ohgami et al., 2005 source

In the paper

“It has also been demonstrated that heme-conjugated iron is absorbed by enterocytes in the duodenum although this heme importer has not yet been characterized (Gräsbeck et al., 1979).”

What the sources say

• Not checked yetcites Gräsbeck et al., 1979 source

In the paper

“This latter step is controlled by the iron exporter, ferroportin (FPN, also called SLC40A1) followed by extracellular oxidation to ferric iron by the copper enzyme hephaestin (HEPH) (Vulpe et al., 1999; Muckenthaler et al., 2017).”

What the sources say

• Not checked yetcites Vulpe et al., 1999 source
• Not checked yetcites Muckenthaler et al., 2017 source

In the paper

“When systemic iron levels in the blood stream are low, expression of DMT1 (divalent metal transporter 1, also called NRAMP2 as well as SLC11A2) and DcytB (duodenal membrane associated cytochrome-b) ferrireductase increases on the surface of intestinal enterocytes on the luminal side enabling the reduction of Fe3+ into its ferrous form (Fe2+) which can then be taken up by DMT1 (McKie et al., 2001).”

What the sources say

• Not checked yetcites McKie et al., 2001 source

In the paper

“Tf-Fe3+ binds to the high-affinity transferrin receptor (TFR1, CD71) on the surface of cells, and this complex is subsequently endocytosed (Harding et al., 1983).”

What the sources say

• Not checked yetcites Harding et al., 1983 source

In the paper

“Hepcidin overexpression leads to low plasma iron levels (hypoferremia) and anemia (Weinstein et al., 2002; Roy et al., 2007; Theurl et al., 2009; Altamura et al., 2014).”

What the sources say

• Not checked yetcites Weinstein et al., 2002 source
• Not checked yetcites Roy et al., 2007 source
• Not checked yetcites Theurl et al., 2009 source

In the paper

“Caenorhabditis elegans fed on a mutant strain of Escherichia coli, which exhibits reduced iron uptake, lead to diminished iron uptake by the worms resulting in significantly impaired mitochondrial ETC function, enhanced ROS production and developmental defects (Zhang et al., 2019).”

What the sources say

• Not checked yetcites Zhang et al., 2019 source

In the paper

“Hepcidin then enters the circulation and binds to the extracellular part of FPN targeting it for degradation, thus preventing iron from being exported into the circulation and instead being sequestered in the cell (Nemeth et al., 2004).”

What the sources say

• Not checked yetcites Nemeth et al., 2004 source

In the paper

“These reports demonstrate how certain cell types rely more heavily on TFR1-mediated iron uptake while other cell types have adapted other mechanisms to import iron into their cells.”

In the paper

“NCOA4 is a key regulator of ferritinophagy and intracellular iron levels—NCOA4-null mice are unable to undergo ferritinophagy and this increased retention of iron within ferritin complexes results in reduced iron export from cells and ultimately in iron-deficient anemia (Bellelli et al., 2014, 2016).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Bellelli et al., 2014, 2016

In the paper

“The Fe source of the cluster is not yet known, although frataxin (FXN) has been identified as an important iron regulator of Fe-S biogenesis (Colin et al., 2013).”

What the sources say

• Not checked yetcites Colin et al., 2013 source

In the paper

“Furthermore, free heme and hemoglobin released during red blood cell (RBC) lysis are bound in the circulation by hemopexin and haptoglobin, respectively, and these iron-containing complexes are then taken up by cells expressing the CD91 and CD163 receptors (Nairz et al., 2017).”

What the sources say

• Not checked yetcites Nairz et al., 2017 source

In the paper

“The key iron exporter is ferroportin (FPN, also called SLC40A1) which exports Fe2+ iron (McKie et al., 2000).”

What the sources say

• Not checked yetcites McKie et al., 2000 source

In the paper

“Frataxin has been proposed to provide the iron while GLRX5 acts not only as a scaffolding protein but may also facilitate the transfer of Fe-S clusters to target proteins (Yoon and Cowan, 2003; Ye et al., 2010).”

What the sources say

• Not checked yetcites Yoon and Cowan, 2003
• Not checked yetcites Ye et al., 2010

In the paper

“Hepatic iron deposits can range from 300 mg to 1 g, but can reach up to 25–30 g in patients suffering from genetic iron overload, a condition called hereditary hemochromatosis (HH) (Janssen and Swinkels, 2009; Anderson and Shah, 2013; Procaccini and Kowdley, 2017).”

What the sources say

• Not checked yetcites Janssen and Swinkels, 2009
• Not checked yetcites Anderson and Shah, 2013
• Not checked yetcites Procaccini and Kowdley, 2017

In the paper

“NF-kB, an important integrator transcription factor downstream from multiple inflammatory signals, as well as NRF2 (nuclear factor erythroid 2-related factor-2), the main stress-responsive transcription factor, both increase ferritin transcription (Miller et al., 1991; Pham et al., 2004).”

What the sources say

• Not checked yetcites Miller et al., 1991 source
• Not checked yetcites Pham et al., 2004 source

In the paper

“Notably, as we discuss later, iron not readily used for metabolic purposes is stored by the protein ferritin and ferritin-conjugated iron released from various cells is taken up by Scara5 (Scavenger receptor class A member 5) or TIM-2 (T Cell Immunoglobulin And Mucin Domain Containing 2) receptors (Chen et al., 2005).”

What the sources say

• Not checked yetcites Chen et al., 2005 source

In the paper

“There also exists a mitochondrial form of ferritin (Levi et al., 2001) which may both protect mitochondria against iron-mediated toxicity and provide a quick and efficient source of iron in this organelle rather than relying solely on the cytosolic ferritin.”

What the sources say

• Not checked yetcites Levi et al., 2001 source

In the paper

“Fe-S clusters are ubiquitous, inorganic co-factors that contribute to a wide range of cellular pathways from genome integrity and gene regulation to energy production and immune responses, and are required for numerous biological functions, particularly enzymatic activity (Beinert, 2000; Johnson et al., 2005; Lee et al., 2009; Fuss et al., 2015).”

What the sources say

• Not checked yetcites Beinert, 2000 source
• Not checked yetcites Johnson et al., 2005 source
• Not checked yetcites Lee et al., 2009 source

In the paper

“Mitochondrial iron is also required for the synthesis of Fe-S clusters and indeed their biogenesis is thought to be one of the most important functions of the mitochondria—even though some Fe-S assembly can occur in the cytosol and nucleus (Tong, 2000; Tong et al., 2003; Tong and Rouault, 2006).”

What the sources say

• Not checked yetcites Tong, 2000 source
• Not checked yetcites Tong et al., 2003 source
• Not checked yetcites Tong and Rouault, 2006

In the paper

“The importance of these oxidases for successful iron export into the circulation has been demonstrated with gene-ablation murine models as well as identification of patients deficient in CP and HEPH, presenting with iron-deficient anemia (Yoshida et al., 1995; Hahn et al., 2004).”

What the sources say

• Not checked yetcites Yoshida et al., 1995 source
• Not checked yetcites Hahn et al., 2004 source

In the paper

“However, pathogens are constantly evolving and adapting to host responses and have created modified siderophores, such as the heavily glycoslyated siderophore, salmochelin, secreted by Salmonella typhimurium, which is not recognized and targeted by lipocalin-2 thus making these bacteria unresponsive to this host defense strategy (Hantke et al., 2003).”

What the sources say

• Not checked yetcites Hantke et al., 2003 source

In the paper

“However, IRP1 binding to the 3′ UTR increases the stability of the respective target mRNAs such as TFR and DMT1, thereby promoting their expression and subsequently enhancing iron uptake into the cell to replenish intracellular iron levels.”

In the paper

“Other related hemoproteins include salivary peroxidase and lactoperoxidase (LPO) which are present in multiple human exocrine secretions, including tears, milk, saliva, and vaginal fluid, and also serves anti-microbial killing actions similar to MPO (Sarr et al., 2018).”

What the sources say

• Not checked yetcites Sarr et al., 2018 source

In the paper

“Erythroferrone (ERFE) is produced by erythropoietin (EPO)-stimulation of erythroid progenitors and blocks hepcidin synthesis in the hepatocytes (Kautz et al., 2014).”

What the sources say

• Not checked yetcites Kautz et al., 2014 source

In the paper

“In addition, neutrophils produce large amounts of calprotectin and lactoferrin, both of which scavenge iron, thereby inhibiting bacterial proliferation (Nakashige et al., 2015).”

What the sources say

• Not checked yetcites Nakashige et al., 2015 source

In the paper

“Conversely, individuals with insufficient hepcidin production, suffer from iron-overload in the blood, and hepatitis (Pietrangelo, 2004).”

What the sources say

• Not checked yetcites Pietrangelo, 2004 source

In the paper

“Indeed, IRP2 deficiency switches cellular metabolic pathways from oxidative phosphorylation (OXPHOS) to aerobic glycolysis (Li et al., 2019) through induction of hypoxia-inducible factors (HIF)-1α and−2α which enhances glycolytic pathway proteins and, at the same time, blocks mitochondrial Fe-S cluster biogenesis and OXPHOS.”

What the sources say

• Not checked yetcites Li et al., 2019

In the paper

“When iron concentrations are low, IRP1 loses it Fe-S cluster and, therefore, its catalytic abilities but instead can now bind to IREs in the 5′ UTR of mRNAs such as ferritin-H and -L subunits as well as the rate-limiting enzyme of heme biogenesis, ALAS (aminolevulinic acid synthase) which results in inhibition of their translation and thus reduced storage and utilization of the metal (Figure 2).”

In the paper

“Siderophores are low molecular weight iron-binding complexes that are secreted by bacteria to compete with transferrin for iron sequestration (Williams, 1988).”

What the sources say

• Not checked yetcites Williams, 1988 source

In the paper

“Superoxide radicals can free up Fe2+ iron and this can further react with hydrogen peroxide (H2O2) to give rise to the hydroxyl radicals (OH•) (Koskenkorva-Frank et al., 2013).”

What the sources say

• Not checked yetcites Koskenkorva-Frank et al., 2013 source

In the paper

“Therefore, the availability and restriction of systemic iron during times of infection and inflammation represents an essential defense mechanism against pathogens but under pathophysiological conditions can lead to anemia and further severe pathologies resulting from reduced RBC development.”

In the paper

“However, when iron levels are low, FBXL5 is itself degraded. This is due to a Fe-binding N-terminal hemerythrin-like (Hr) iron-sensing domain in FBXL5. The Hr domain undergoes a conformational change when iron is not present—this structural change leads to FBXL5 polyubiquitination and degradation resulting in IRP2 accumulation (Thompson et al., 2012).”

What the sources say

• Not checked yetcites Thompson et al., 2012 source

In the paper

“Imbalanced iron levels in the cell can lead to dysfunctional mitochondria, increased oxidative damage and increased toxicity (Richardson et al., 2010; Volani et al., 2017).”

What the sources say

• Not checked yetcites Richardson et al., 2010 source
• Not checked yetcites Volani et al., 2017 source

In the paper

“When iron levels normalize again, IRP1 regains its Fe-S cluster and aconitase activity. This results in increased ferritin translation and decreased TFR expression, resulting in reduced Fe uptake (Li et al., 2004; Rouault, 2006; Leipuviene and Theil, 2007; Sanchez et al., 2011; Figure 2).”

What the sources say

• Not checked yetcites Li et al., 2004
• Not checked yetcites Rouault, 2006 source
• Not checked yetcites Leipuviene and Theil, 2007

In the paper

“Macrophages and Kupffer cells scavenge heme from damaged or aged RBCs in the bone marrow, liver and spleen, and extract the Fe2+ iron using HO-1 and then either exports it back into the circulation through FPN or stores it in ferritin intracellularly (Knutson et al., 2005; Theurl et al., 2016).”

What the sources say

• Not checked yetcites Knutson et al., 2005 source
• Not checked yetcites Theurl et al., 2016 source

In the paper

“Furthermore, hematopoietic-specific deletion of the ferritin heavy chain (Fth) gene results in reduced numbers of lymphocytes while other cell types such as granulocytes and monocytes are unaffected, again highlighting the essential nature of iron regulation to the adaptive immune system (Vanoaica et al., 2014).”

What the sources say

• Not checked yetcites Vanoaica et al., 2014 source

In the paper

“In mice, this is done by increased production of nitric oxide (NO) (Nairz et al., 2013), which activates the stress-responsive transcription factor, NRF2 resulting in transcriptional induction of FPN expression leading to subsequent increase of iron export from the cell, thus again restricting iron availability to the intracellular pathogen.”

What the sources say

• Not checked yetcites Nairz et al., 2013 source

In the paper

“Ablation of Fth leads to an increase in the labile iron pool (LIP) within the cell contributing to increased oxidative stress and cell death, though when cells are stimulated the increased availability of Fe2+ iron enhances proliferative capacity before ultimately undergoing cell death, possibly due to proliferating cells using up the excess iron (Vanoaica et al., 2014).”

What the sources say

• Not checked yetcites Vanoaica et al., 2014 source

In the paper

“However, degeneration of cells in the brain also result in the deposition of iron in the extracellular space, which then induces waves of oxidative stress (via Fenton chemistry) in these brain regions (Craelius et al., 1982; Bagnato et al., 2011).”

What the sources say

• Not checked yetcites Craelius et al., 1982
• Not checked yetcites Bagnato et al., 2011 source

In the paper

“However, unlike neutrophils which release MPO into the phagosome, eosinophils release their EPX-containing granules extracellularly to kill parasites to which they are attached (Acharya and Ackerman, 2014).”

What the sources say

• Not checked yetcites Acharya and Ackerman, 2014

In the paper

“Patients with iron-overload in beta-thalassemia major have decreased CD4+ T cells but increased CD8+ T cell numbers (Porto and De Sousa, 2007), while patients suffering from hereditary hemochromatosis (HH) have apparently normal CD4+ and reduced CD8+ numbers, with the latter displaying a more “effector” phenotype, suggesting again that increased intracellular iron availability may have hyper-prol”

What the sources say

• Not checked yetcites Porto and De Sousa, 2007

In the paper

“However, in the context of the tumor microenvironment (TME), the situation is quite complicated as M2 TAMs (tumor-infiltrating macrophages) which are “iron-releasing” will support tumor growth while M1 “iron-retaining” limit tumor progression (Jung et al., 2019).”

What the sources say

• Not checked yetcites Jung et al., 2019 source

In the paper

“NRAMP1 acts as a transporter for divalent metals, including iron, and promotes iron export from the phagolyosome and then from the cytoplasm by induction of FPN expression (Nairz et al., 2007; Lim et al., 2018).”

What the sources say

• Not checked yetcites Nairz et al., 2007 source
• Not checked yetcites Lim et al., 2018 source

In the paper

“This allows the M2 macrophages to promote iron recirculation and aid in tissue healing, a process which requires large amount of iron to rebuild damaged tissue (Recalcati et al., 2010a).”

What the sources say

• Not checked yetcites Recalcati et al., 2010a

In the paper

“Interestingly, eosinophils have a homolog of MPO called eosinophil peroxidase (EPX) which shares ~70% similarity at the amino acid level with neutrophilic MPO (Ten et al., 1989).”

What the sources say

• Not checked yetcites Ten et al., 1989

In the paper

“Thus, HO-1 exerts cytoprotective effects by reducing the pro-oxidative activity of heme and by re-programming metabolic traits, thereby limiting tissue damage in the course of inflammatory processes, including sepsis (Gozzelino et al., 2010; Weis et al., 2017).”

What the sources say

• Not checked yetcites Gozzelino et al., 2010 source
• Not checked yetcites Weis et al., 2017 source

In the paper

“Such microglial dystrophy has been observed in Alzheimer's brains as well as aged brains (Lopes et al., 2008).”

What the sources say

• Not checked yetcites Lopes et al., 2008 source

In the paper

“Indeed within a minute of T cell receptor (TCR) engagement, surface TFR is upregulated from endosomal compartments and is localized to the immunological synapse (IS), the receptor-filled contact area between an antigen-presenting cell and a T cell, necessary for full T cell activation (Batista et al., 2004).”

What the sources say

• Not checked yetcites Batista et al., 2004 source

In the paper

“In lung cancer for example, iron-laden TAMs have been demonstrated to enhance production of ROS and pro-inflammatory cytokines (TNFα and IL-6) and to directly kill tumor cells (da Silva et al., 2017), prompting the exciting possibility of delivering iron to TAMs as a simple adjuvant therapeutic strategy.”

What the sources say

• Not checked yetcites da Silva et al., 2017 source

In the paper

“Heme scavenging proteins such as hemopexin can bind free heme, thus clearing it from the circulation and delivering it to cells (Smith et al., 1988).”

What the sources say

• Not checked yetcites Smith et al., 1988 source

In the paper

“In contrast, M1 macrophages enhance iron uptake and storage, and display an attenuated iron-release phenotype favoring intracellular iron sequestration and storage, which has been shown to enhance antimicrobial effector functions such as increased pro-inflammatory TNFα expression while suppressing expression of the anti-inflammatory cytokine, IL-10 (Weiss et al., 1994; Mulero et al., 2002; Fritsch”

What the sources say

• Not checked yetcites Weiss et al., 1994 source
• Not checked yetcites Mulero et al., 2002 source
• Not checked yetcites Fritsche et al., 2008 source

In the paper

“GTP cyclohydrolase I (GCH1) is the rate-limiting enzyme for BH4 biosynthesis (Werner et al., 2011; Figure 4).”

What the sources say

• Not checked yetcites Werner et al., 2011 source

In the paper

“Levels of intracellular iron were increased significantly in SLE CD4+ T cells compared to healthy controls and the researchers suggest a link between iron homeostasis and global DNA methylation status (Zhao et al., 2018), by which SLE T cells exhibit reduced DNA demethylation resulting in enhanced immune-related gene expression.”

What the sources say

• Not checked yetcites Zhao et al., 2018 source

In the paper

“GM-CSF is essential for the development and progression of EAE. Mice deficient in GM-CSF are resistant to EAE induction, and blockade of GM-CSF in wild-type mice suppresses ongoing disease (McQualter et al., 2001; Codarri et al., 2011).”

What the sources say

• Not checked yetcites McQualter et al., 2001 source
• Not checked yetcites Codarri et al., 2011 source

In the paper

“suggesting that BH4 deficiency affects iron metabolism and the cell compensates by trying to increase Fe2+ levels in the mitochondria.”

In the paper

“Ferroptosis is an iron-dependent oxidative form of cell death associated with increased lipid peroxidation (Xie et al., 2016).”

What the sources say

• Not checked yetcites Xie et al., 2016 source

In the paper

“It was demonstrated that iron protects PCBP1 (Poly(RC)-binding protein 1), an RNA binding protein which stabilizes GMCSF mRNA, from caspase-mediated proteolysis thus leading to enhanced GMCSF production when iron levels are high within the T cell to drive inflammation (Wang et al., 2018).”

What the sources say

• Not checked yetcites Wang et al., 2018 source

In the paper

“Through these enzymes, BH4 is required for nitric oxide (NO) production, metabolism of ether lipids, phenylalanine catabolism, and synthesis of the amine neurotransmitters norepinephrine, epinephrine, serotonin, and dopamine.”

What the sources say

• Not checked yetcites Werner et al., 2011 source

In the paper

“Moreover, ferroptosis can be blocked with iron chelators but not with inhibitors of apoptosis and necroptosis (Xie et al., 2016).”

What the sources say

• Not checked yetcites Xie et al., 2016 source

In the paper

“A common phenotype of defective Fe-S biogenesis is mitochondrial iron loading, resulting in mitochondrial dysfunction and oxidative stress (Reeve et al., 2012).”

What the sources say

• Not checked yetcites Reeve et al., 2012 source

In the paper

“while patients suffering from hereditary hemochromatosis (HH) have apparently normal CD4+ and reduced CD8+ numbers, with the latter displaying a more “effector” phenotype, suggesting again that increased intracellular iron availability may have hyper-proliferative effects in T cells, although this may well-depend on which oxidation form of Fe is available (Costa et al., 2015).”

What the sources say

• Not checked yetcites Costa et al., 2015 source

In the paper

“Intriguingly, sulfasalazine, a drug used for decades to treat autoimmune inflammatory bowel disease (IBD) and psoriatic arthritis (Gupta et al., 1990), is now recognized as targeting the BH4 pathway by inhibiting SPR (Haruki et al., 2013), in addition to other targets, such as NFκB (Wahl et al., 1998).”

What the sources say

• Not checked yetcites Gupta et al., 1990 source

In the paper

“IFNγ has a strong regulatory role in iron homeostasis as it enhances the expression of cellular iron-regulating genes such as HO-1 but also reduces the iron-exporting gene ferroportin (Ludwiczek et al., 2003; Nairz et al., 2015).”

What the sources say

• Not checked yetcites Ludwiczek et al., 2003 source
• Not checked yetcites Nairz et al., 2015 source

In the paper

“Intriguingly, sulfasalazine, a drug used for decades to treat autoimmune inflammatory bowel disease (IBD) and psoriatic arthritis (Gupta et al., 1990), is now recognized as targeting the BH4 pathway by inhibiting SPR (Haruki et al., 2013), in addition to other targets, such as NFκB (Wahl et al., 1998).”

What the sources say

• Not checked yetcites Wahl et al., 1998 source

In the paper

“Interestingly, high doses of sulfasalazine are associated with RBC abnormalities (Pounder et al., 1975).”

What the sources say

• Not checked yetcites Pounder et al., 1975 source

In the paper

“Targeting this pathway offers a novel therapeutic and new mode-of-action opportunity to control T cell proliferation, and in this way help to control autoimmunity or enhance anti-cancer immunity.”

What the sources say

• Not checked yetcites Cronin et al., 2018 source

In the paper

“A general decrease in Fe3+ reduction resulting in a scarcity of Fe2+ and increase of Fe3+ would affect many aspects of cellular metabolism (Volani et al., 2017) which contribute to the reduced T cell proliferation observed with BH4-deficiency.”

What the sources say

• Not checked yetcites Volani et al., 2017 source