Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages

Harada, Nobuhiko; Kanayama, Masaya; Maruyama, Atsushi; Yoshida, Aruto; Tazumi, Kyoko; Hosoya, Takamitsu; Mimura, Junsei; Toki, Tsutomu; Maher, Jonathan; Yamamoto, Masayuki; Itoh, Ken

doi:10.1016/j.abb.2011.02.001

Cited by 187 publications

(122 citation statements)

References 52 publications

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“…]NTA in the presence of 10 lM pyrithione did not significantly change their viability. These data corroborate a recent concept on crucial role of Nrf2 and NFjB (p65) in adaptive response to oxidative and electrophilic stresses, and regulation of cell iron homeostasis (Kobayashi et al 2006;Harada et al 2011).…”

Section: Assessment Of [Fesupporting

confidence: 91%

Iron-induced remodeling in cultured rat pulmonary artery endothelial cells

et al. 2011

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Although iron is known to be a component of the pathogenesis and/or maintenance of acute lung injury (ALI) in experimental animals and human subjects, the majority of these studies have focused on disturbances in iron homeostasis in the airways resulting from exposure to noxious gases and particles. Considerably less is known about the effect of increased plasma levels of redox-reactive non-transferrin bound iron (NTBI) and its impact on pulmonary endothelium. Plasma levels of NTBI can increase under various pathophysiological conditions, including those associated with ALI, and multiple mechanisms are in place to affect the [Fe(2+)]/[Fe(3+)] redox steady state. It is well accepted, however, that intracellular transport of NTBI occurs after reduction of [Fe(3+)] to [Fe(2+)] (and is mediated by divalent metal transporters). Accordingly, as an experimental model to investigate mechanisms mediating vascular effects of redox reactive iron, rat pulmonary artery endothelial cells (RPAECs) were subjected to pulse treatment (10 min) with [Fe(2+)] nitriloacetate (30 μM) in the presence of pyrithione, an iron ionophore, to acutely increase intracellular labile pool of iron. Cellular iron influx and cell shape profile were monitored with time-lapse imaging techniques. Exposure of RPAECs to [Fe(2+)] resulted in: (i) an increase in intracellular iron as detected by the iron sensitive fluorophore, PhenGreen; (ii) depletion of cell glutathione; and (iii) nuclear translocation of stress-response transcriptional factors Nrf2 and NFkB (p65). The resulting iron-induced cell alterations were characterized by cell polarization and formation of membrane cuplike and microvilli-like projections abundant with ICAM-1, caveolin-1, and F-actin. The iron-induced re-arrangements in cytoskeleton, alterations in focal cell-cell interactions, and cell buckling were accompanied by decrease in electrical resistance of RPAEC monolayer. These effects were partially eliminated in the presence of N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid, an iron chelator, and Y27632, a Rho-kinase inhibitor. Thus acute increases in labile iron in cultured pulmonary endothelium result in structural remodeling (and a proinflammatory phenotype) that occurs via post-transcriptional mechanisms regulated in a redox sensitive fashion.

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Section: Assessment Of [Fesupporting

confidence: 91%

Iron-induced remodeling in cultured rat pulmonary artery endothelial cells

et al. 2011

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“…Under conditions of low iron, Fpn induction requires the HIF family member HIF-2α and disruption of this signal impairs Fpn expression [74]. The redox sensitive transcription factor Nf2 is also found to regulate Fpn induction leading to the mediation of iron flux [75].…”

Section: Resultsmentioning

confidence: 99%

Evaluating Iron Flux in the Brain

Wong

Lam

Tsatsanis

et al. 2017

Metals in the Brain

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Regulated efflux of iron from cells is a fundamental event in controlling the intracellular pool of labile iron. Imbalance to this pool can be detrimental to the cell either through impairment to metabolic pathways when deficient or production of hydroxyl radicals when in excess. While ferroportin is currently the only known iron export pore protein in all cell types of the brain, its functional location is established through protein complexes that vary between cell types. Here, we describe selected experimental techniques that can evaluate iron flux as well as the downstream changes to the labile intracellular pool of iron within the whole brain or select cell types. Our aim is to provide the reader with previously applied procedures using resources available in most biochemical laboratories for interrogating cellular location and movement of iron in cells and tissue that has derived from brain.

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“…Ribosomal Stress-activated p38 Signaling Regulates FPN-1-promoting NRF2 and NF-B-Among the known transcription factors in FPN-1 transcription, nuclear factor erythroid 2-like (NRF2) binds to antioxidant response elements (AREs)/Maf recognition elements (MAREs) with small Maf protein (sMAF) within the FPN-1 promoter (-7007/-7016) (18,40). NF-B is also an important pro-inflammatory transcription factor within the FPN-1 promoter to induce FPN-1 expression (Fig.…”

Section: P38 Mapk Signaling Is Critical For Fpn Suppression and Subsementioning

confidence: 99%

“…In particular, FPN1B is mainly expressed in enterocytes and erythroid precursors, which are able to export intracellular iron when iron deficiency occurs (17). In addition to posttranscriptional repression, transcriptional and posttranslational regulation are involved in FPN expression in other cells and tissues (18,19). Patients with genetic mutations in the FPN gene develop hemochromatosis.…”

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confidence: 99%

Non-mutagenic Suppression of Enterocyte Ferroportin 1 by Chemical Ribosomal Inactivation via p38 Mitogen-activated Protein Kinase (MAPK)-mediated Regulation

Park

Kim

et al. 2016

Journal of Biological Chemistry

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Iron transfer across the basolateral membrane of an enterocyte into the circulation is the rate-limiting step in iron absorption and is regulated by various pathophysiological factors. Ferroportin (FPN), the only known mammalian iron exporter, transports iron from the basolateral surface of enterocytes, macrophages, and hepatocytes into the blood. Patients with genetic mutations in FPN or repeated blood transfusion develop hemochromatosis. In this study, non-mutagenic ribosomal inactivation was assessed as an etiological factor of FPN-associated hemochromatosis in enterocytes. Non-mutagenic chemical ribosomal inactivation disrupted iron homeostasis by regulating expression of the iron exporter FPN-1, leading to intracellular accumulation in enterocytes. Mechanistically, a xenobiotic insult stimulated the intracellular sentinel p38 MAPK signaling pathway, which was positively involved in FPN-1 suppression by ribosomal dysfunction. Moreover, ribosomal inactivation-induced iron accumulation in Caenorhabditis elegans as a simplified in vivo model for gut nutrition uptake was dependent on SEK-1, a p38 kinase activator, leading to suppression of FPN-1.1 expression and iron accumulation. In terms of gene regulation, ribosomal stress-activated p38 signaling down-regulated NRF2 and NF-B, both of which were positive transcriptional regulators of FPN-1 transcription. This study provides molecular evidence for the modulation of iron bioavailability by ribosomal dysfunction as a potent etiological factor of non-mutagenic environmental hemochromatosis in the gut-to-blood axis.

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Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages

Cited by 187 publications

References 52 publications

Iron-induced remodeling in cultured rat pulmonary artery endothelial cells

Iron-induced remodeling in cultured rat pulmonary artery endothelial cells

Evaluating Iron Flux in the Brain

Non-mutagenic Suppression of Enterocyte Ferroportin 1 by Chemical Ribosomal Inactivation via p38 Mitogen-activated Protein Kinase (MAPK)-mediated Regulation

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