Alessandro Matte1, Luigia De Falco2, Enrica Federti1, Anna Cozzi3, Achille Iolascon2, Sonia Levi3,4, Narla Mohandas5, Alberto Zamo6, Mariasole Bruno2, Christophe Lebouef7, Anne Janin7,8,9, Angela Siciliano1, Tom Ganz10, Giorgia Federico11, Francesca Carlomagno11, Sebastian Mueller12, Ines Silva12, Carmine Carbone1, Davide Melisi1, Dae Won Kim13, Soo Young Choi13, Lucia De Franceschi1. 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.
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.
Entities:
Keywords:
hepcidin; iron overload; peroxiredoxin-2
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