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

Abstract

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates cell-intrinsic protective antioxidant responses, while the peptide hormone hepcidin maintains systemic iron homoeostasis, but is pathophysiologically decreased in haemochromatosis and β-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives bone morphogenetic protein 6 (Bmp6) expression in liver sinusoidal endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6–hepcidin response to oral and parenteral iron is impaired, and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6–hepcidin axis, improving iron homoeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in β-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to the control of systemic iron homoeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders.

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The datasets generated and/or analysed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank the staff of the University of Oxford Department of Biomedical Services for animal husbandry, M. Nairz (Medical University of Innsbruck) for assistance with flow cytometry and A. Townsend (Weatherall Institute of Molecular Medicine) for helpful advice and discussions. This work was supported by the UK Medical Research Council (MRC Human Immunology Unit core funding to H.D., award no. MC_UU_12010/10) and Radcliffe Department of Medicine (RDM Scholars Program to P.J.L.). The work conducted at the Instituto de Biologia Molecular e Celular was supported by FEDER funds through COMPETE and by Portuguese funds through Fundação para a Ciência e Tecnologia (grant nos. PTDC/BIM-MET/0739/2012 and SFRH/BPD/108207/2015 to T.L.D.), and the Norte 2020 Portugal Regional Operational Programme (grant no. Norte-01-0145-FEDER-000012). J.L.B. was supported by the National Institutes of Health (grant no. RO1-DK087727) and Massachusetts General Hospital (Howard Goodman Award). Work in M.P.M.’s lab is supported by the Medical Research Council UK (grant no. MC_U105663142) and by a Wellcome Trust Investigator award (no. 110159/Z/15/Z). A.M.H., D.G.S. and P.P. were funded by grants from the Canadian Institutes of Health Research (grant nos. MOP-14100 and MOP-126064).

Author information

P.J.L., T.L.D., C.B.W., D.G.S., P.P., A.E.A., S.R.P. and H.D. designed the research. P.J.L., T.L.D., A.E.A., J.A., H.M., D.G.S., A.H., S.W., S.R.P., J.R.H., A.G.S., A.L.B., A.S.G., A.M., E.S., C.Y.W. and J.L.B. collected the data. P.J.L., H.D., T.L.D., D.G.S., P.P., P.K., A.E.A., S.R.P., E.S., R.C.H., M.P.M., C.Y.W., J.L.B. and G.P. analysed and interpreted the data. P.J.L. and H.D. wrote the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Hal Drakesmith.

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Fig. 1: The transcription factor Nrf2 regulates Bmp6 gene expression.
Fig. 2: Iron induces oxidative stress to activate Nrf2 and upregulate Bmp6 expression.
Fig. 3: Induction of Bmp6 and hepcidin by iron is blunted in the absence of Nrf2. Nrf2 knockout mice load with more hepatic iron.
Fig. 4: Liver and LSEC mitochondrial pathology in iron-loaded Nrf2−/− mice.
Fig. 5: The small-molecule Nrf2 agonist CDDO-Im alleviates iron accumulation in Hfe knockout haemochromatosis mice.
Fig. 6: CDDO-Im alters the Bmp6–erythroferrone axis and decreases serum iron in mice with thalassaemia.