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

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

Research output: Contribution to journalArticlepeer-review

72 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)101-109
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume508
Issue number1
DOIs
Publication statusPublished - 2011 Apr 1

Keywords

  • Ferroportin 1
  • Inflammation
  • Iron metabolism
  • Macrophage
  • Nrf2

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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