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

2017; Mary Ann Liebert, Inc.; Volume: 28; Issue: 1 Linguagem: Inglês

10.1089/ars.2017.7051

1557-7716

Alessandro Mattè, Luigia De Falco, Enrica Federti, Anna Cozzi, Achille Iolascon, Sonia Levi, Narla Mohandas, Alberto Zamò, Mariasole Bruno, Christophe Lebouef, Anne Janin, Angela Siciliano, Tomas Ganz, Giorgia Federico, Francesca Carlomagno, Sebastian Mueller, Inês Pires da Silva, Carmine Carbone, Davide Melisi, Dae Won Kim, Soo Young Choi, Lucia De Franceschi,

Hemoglobinopathies and Related Disorders

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.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.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.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.