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Antioxid Redox Signal. 2018 Jan 1;28(1):1-14. doi: 10.1089/ars.2017.7051. Epub 2017 Sep 6.

Peroxiredoxin-2: A Novel Regulator of Iron Homeostasis in Ineffective Erythropoiesis.

Author information

1
1 Department of Medicine, University of Verona-AOUI Verona , Verona, Italy .
2
2 CEINGE and Department of Biochemistry, Federico II University , Naples, Italy .
3
3 Division of Neuroscience, San Raffaele Scientific Institute , Milano, Italy .
4
4 Vita-Salute San Raffaele University , Milano, Italy .
5
5 New York Blood Center , New York, New York.
6
6 Department of Pathology and Diagnostic University of Verona-AOUI Verona , Verona, Italy .
7
7 Inserm, U1165, Paris, France .
8
8 Université Paris 7-Denis Diderot , Paris, France .
9
9 AP-HP , Hôpital Saint-Louis, Paris, France .
10
10 Department of Pathology and Laboratory of Medicine, UCLA School of Medicine , Los Angeles, California.
11
11 Department of Molecular Medicine and Medical Biotechnologies Federico II University , Naples, Italy .
12
12 Medical Department, Salem Medical Center, University of Heidelberg , Heidelberg, Germany .
13
13 Department of Biomedical Sciences, Institute of Bioscience and Biotechnology, Hallym University , Chunchon, Korea.

Abstract

AIMS:

Iron overload (IO) is a life-threatening complication of chronic hemolytic disorders such as β-thalassemia. IO results in severe cellular oxidative damage, leading to organ failure. Peroxiredoxin-2 (Prx2), a typical 2-cysteine-(Cys)-peroxiredoxin, is an important component of the cytoprotective system, but its response to IO is still to be fully defined.

RESULTS:

We studied the effects of IO on Prx2-knockout mice (Prx2-/-). The absence of Prx2 enhanced toxicity due to IO on erythropoiesis. We found that IO failed to induce the typical hepcidin (Hamp) upregulation in Prx2-/- mice due to its failure to activate the signal transducer and activator of transcription-3 (STAT3) with intact Jak2 signaling. In Prx2-/- mice, the loss of Hamp response was also observed after administration of a single dose of oral iron. When lipopolysaccharide (LPS) was used to explore IL6-STAT3 activation in Prx2-/- mice, STAT3 activation and Hamp upregulation were once again defective. Treatment with PEP-fusion-recombinant-Prx2 (PEP Prx2) significantly increased STAT3 activation with upregulation of Hamp expression in both IO- and LPS-exposed Prx2-/- mice. We also confirmed the beneficial effects of PEP Prx2 on Hamp expression through STAT3 activation in β-thalassemic mice.

INNOVATION:

We propose that Prx2 plays a key role in responding to cytotoxicity of IO, directly targeting STAT3-transcriptional factor in a Jak2-independent fashion and regulating Hamp in response to canonical stimuli.

CONCLUSION:

Collectively, our data highlight a novel role of Prx2 in iron homeostasis. Prx2 is a key cytoprotector against IO that is induced either by iron supplementation or due to chronic hemolysis as in β-thalassemia. Prx2 is required to support STAT3 transcriptional activity and regulation of Hamp expression. Antioxid. Redox Signal. 28, 1-14.

KEYWORDS:

hepcidin; iron overload; peroxiredoxin-2

PMID:
28793778
DOI:
10.1089/ars.2017.7051
[Indexed for MEDLINE]

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