title: Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages.
abstract: Iron is an essential element of hemoglobin, and efficient iron recycling from senescent erythrocytes by splenic macrophages is required for erythrocyte hemoglobin synthesis during erythropoiesis. Ferroportin 1 (Fpn1) is the sole iron exporter in mammals, and it also regulates iron reutilization. In this study, we demonstrated genetically that a redox-sensitive transcription factor, Nrf2, regulates Fpn1 mRNA expression in macrophages. Nrf2 activation by several electrophilic compounds commonly resulted in the upregulation of Fpn1 mRNA in bone marrow-derived and peritoneal macrophages obtained from wild-type mice but not from Nrf2 knockout mice. Further, Nrf2 activation enhanced iron release from the J774.1 murine macrophage cell line. Previous studies showed that inflammatory stimuli, such as LPS, downregulates macrophage Fpn1 by transcriptional and hepcidin-mediated post-translational mechanisms leading to iron sequestration by macrophages. We showed that two Nrf2 activators, diethyl maleate and sulforaphane (SFN; a natural Nrf2 activator found in broccoli), restored the LPS-induced suppression of Fpn1 mRNA in human and mouse macrophages, respectively. Furthermore, SFN counteracted the LPS-induced increase of Hepcidin mRNA by an Nrf2-independent mechanism in mouse peritoneal macrophages. These results demonstrate that Nrf2 regulates iron efflux from macrophages through Fpn1 gene transcription and suggest that Nrf2 may control iron metabolism during inflammation.
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Harada
authors.forename: Masaya
authors.initials: M
authors.lastname: Kanayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maruyama
authors.forename: Aruto
authors.initials: A
authors.lastname: Yoshida
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tazumi
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hosoya
authors.forename: Junsei
authors.initials: J
authors.lastname: Mimura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Toki
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Maher
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D064451:Hepcidins; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D017879:Isothiocyanates; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000098742:Ferroportin; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D051547:Heme Oxygenase-1; D064451:Hepcidins; D007501:Iron; D017879:Isothiocyanates; D008070:Lipopolysaccharides; D008298:Maleates; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D013454:Sulfoxides; D013861:Thiocyanates; D000098742:Ferroportin; D000099173:Natural Resistance-associated Macrophage Protein 1; C578702:HAMP protein, human; C579599:Hamp protein, mouse; C014476:diethyl maleate; C016766:sulforaphane