Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin

Lim, Pei Jin; Duarte, Tiago; Arezes, João; Garcia-Santos, Daniel; Hamdi, Amel; Pasricha, Sant‐Rayn; Armitage, Andrew E.; Mehta, Hema; Wideman, Sarah; Santos, Ana Lúcia; Santos-Gonçalves, Andreia; Morovat, Alireza; Hughes, Jim R.; Soilleux, Elizabeth; Wang, Chia-Yu; Bayer, Abraham L; Klenerman, Paul; Willberg, Christian; Hartley, Richard C.; Murphy, Michael P.; Babitt, Jodie L.; Ponka, Prem; Porto, Graça; Drakesmith, Hal

doi:10.1038/s42255-019-0063-6

Cited by 97 publications

(119 citation statements)

References 57 publications

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“…[12][13][14] Hepcidin expression is modulated by the BMP/SMAD signaling pathway: binding of bone morphogenetic proteins (BMPs) to BMP receptors in the membrane of hepatocytes causes phosphorylation of cytosolic SMADs (SMAD1/5/8) that translocate to the nucleus complexed with SMAD4 to activate the transcription of target genes, including hepcidin (HAMP). [15][16][17] This pathway is activated in response to iron via BMP6 18,19 and by BMP2 independently of BMP6. 20 Hepcidin suppression during erythropoiesis is mediated at least in part by erythroferrone (ERFE), a protein synthesized in erythroblasts in response to erythropoietin (EPO), downstream of JAK2-STAT5 signaling.…”

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confidence: 99%

Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia

Arezes

Foy

McHugh

et al. 2020

Blood

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Erythroferrone (ERFE) is produced by erythroblasts in response to erythropoietin (EPO) and acts in the liver to prevent hepcidin stimulation by BMP6. Hepcidin suppression allows for the mobilization of iron to the bone marrow for the production of red blood cells. Aberrantly high circulating ERFE in conditions of stress erythropoiesis, such as in patients with β-thalassemia, promotes the tissue iron accumulation that substantially contributes to morbidity in these patients. Here we developed antibodies against ERFE to prevent hepcidin suppression and to correct the iron loading phenotype in a mouse model of β-thalassemia [Hbb(th3/+) mice] and used these antibodies as tools to further characterize ERFE’s mechanism of action. We show that ERFE binds to BMP6 with nanomolar affinity and binds BMP2 and BMP4 with somewhat weaker affinities. We found that BMP6 binds the N-terminal domain of ERFE, and a polypeptide derived from the N terminus of ERFE was sufficient to cause hepcidin suppression in Huh7 hepatoma cells and in wild-type mice. Anti-ERFE antibodies targeting the N-terminal domain prevented hepcidin suppression in ERFE-treated Huh7 cells and in EPO-treated mice. Finally, we observed a decrease in splenomegaly and serum and liver iron in anti–ERFE-treated Hbb(th3/+) mice, accompanied by an increase in red blood cells and hemoglobin and a decrease in reticulocyte counts. In summary, we show that ERFE binds BMP6 directly and with high affinity, and that antibodies targeting the N-terminal domain of ERFE that prevent ERFE–BMP6 interactions constitute a potential therapeutic tool for iron loading anemias.

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confidence: 99%

Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia

Arezes

Foy

McHugh

et al. 2020

Blood

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“…Indeed, macrophages, in addition to their key role in the initiation and sustainability of the inflammatory response, have a central role in the management of iron homeostasis. This link between inflammatory response, pathogen defense and iron homeostasis control has already been documented [53][54][55][56][57].…”

Section: Discussionmentioning

confidence: 70%

Influences of Nanoparticles Characteristics on the Cellular Responses: The Example of Iron Oxide and Macrophages

et al. 2020

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Iron oxide nanoparticles/microparticles are widely present in a variety of environments, e.g., as a byproduct of steel and iron degradation, as, for example, in railway brakes (e.g., metro station) or in welding fumes. As all particulate material, these metallic nanoparticles are taken up by macrophages, a cell type playing a key role in the innate immune response, including pathogen removal phagocytosis, secretion of free radical species such as nitric oxide or by controlling inflammation via cytokine release. In this paper, we evaluated how macrophages functions were altered by two iron based particles of different size (100 nm and 20 nm). We showed that at high, but subtoxic concentrations (1 mg/mL, large nanoparticles induced stronger perturbations in macrophages functions such as phagocytic capacity (tested with fluorescent latex microspheres) and the ability to respond to bacterial endotoxin lipopolysaccharide stimulus (LPS) in secreting nitric oxide and pro-cytokines (e.g., Interleukin-6 (IL-6) and Tumor Necrosis Factor (TNF)). These stronger effects may correlate with an observed stronger uptake of iron for the larger nanoparticles.

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“…However, the exact mechanism underlying the regulation of BMP6 gene expression in liver is largely unknown. In a recent study, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) was reported to regulate hepatic BMP6 expression in response to iron by directly binding the BMP6 gene promoter [ 36 ]. Here, we show that orphan nuclear receptor ERRγ transcriptionally regulates hepatic BMP6 expression by directly binding the ERRE motif in the BMP6 gene promoter, in response to IL-6 treatment.…”

Section: Discussionmentioning

confidence: 99%

“…NPCs include hepatic stellate cells, Kupffer cells and liver sinusoidal epithelial cells. Hepatic BMP6 production was reported from NPCs in several reports [ 36 , 38 , 39 ]. In particular, it was reported that BMP6 basal expression was confined to NPCs, namely HSCs and KCs, and treatment with TGF-β1 increased BMP6 gene expression in HSCs [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice

Radhakrishnan

Kim

Jung

et al. 2020

IJMS

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Bone morphogenetic protein 6 (BMP6) is a multifunctional growth factor involved in organ development and homeostasis. BMP6 controls expression of the liver hormone, hepcidin, and thereby plays a crucial role in regulating iron homeostasis. BMP6 gene transcriptional regulation in liver is largely unknown, but would be of great help to externally modulate iron load in pathologic conditions. Here, we describe a detailed molecular mechanism of hepatic BMP6 gene expression by an orphan nuclear receptor, estrogen-related receptor γ (ERRγ), in response to the pro-inflammatory cytokine interleukin 6 (IL-6). Recombinant IL-6 treatment increases hepatic ERRγ and BMP6 expression. Overexpression of ERRγ is sufficient to increase BMP6 gene expression in hepatocytes, suggesting that IL-6 is upstream of ERRγ. In line, knock-down of ERRγ in cell lines or a hepatocyte specific knock-out of ERRγ in mice significantly decreases IL-6 mediated BMP6 expression. Promoter studies show that ERRγ directly binds to the ERR response element (ERRE) in the mouse BMP6 gene promoter and positively regulates BMP6 gene transcription in IL-6 treatment conditions, which is further confirmed by ERRE mutated mBMP6-luciferase reporter assays. Finally, an inverse agonist of ERRγ, GSK5182, markedly inhibits IL-6 induced hepatic BMP6 expression in vitro and in vivo. Taken together, these results reveal a novel molecular mechanism on ERRγ mediated transcriptional regulation of hepatic BMP6 gene expression in response to IL-6.

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Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin

Cited by 97 publications

References 57 publications

Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia

Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia

Influences of Nanoparticles Characteristics on the Cellular Responses: The Example of Iron Oxide and Macrophages

Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice

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