The interplay between peroxiredoxin-2 and Nrf2 is important in limiting oxidative mediated dysfunction in b-thalassemic erythropoiesis

Aims: b-Thalassemia is a common inherited red cell disorder characterized by ineffective erythropoiesis andsevere oxidative stress. Peroxiredoxin-2 (Prx2), a typical 2-cysteine peroxiredoxin, is upregulated during bthalassemicerythropoiesis, but its contribution to stress erythropoiesis, a common feature of thalassemia, is yetto be fully defined. Results: Here, we showed that Prx2-/ - mice displayed reactive oxygen species relatedabnormalities in erythropoiesis similar to that of Hbbth3/+ mice associated with activation of redox responsetranscriptional factor nuclear factor-erythroid 2 (Nrf2). We generated b-thalassemic mice genetically lackingPrx2 (Prx2-/ -Hbbth3/+) and documented a worsened b-thalassemic hematological phenotype with severe ineffectiveerythropoiesis. To further validate a key role of Prx2 in stress erythropoiesis, we administrated fusedrecombinant PEP1Prx2 to Hbbth3/+ mice and documented a decrease in ineffective erythropoiesis. We furthershow that Prx2 effects are mediated by activation of Nrf2 and upregulation of genes that protect againstoxidative damage such as gluthatione S-transferase, heme-oxygenase-1, and NADPH dehydrogenase quinone-1.Innovation: We propose Prx2 as a key anti-oxidant system and Nrf2 activation is a cellular adaptive process inresponse to oxidative stress, resulting in upregulation of anti-oxidant (anti-oxidant responsive element) genesrequired to ensure cell survival. Conclusion: Our data shed new light on adaptive mechanisms against oxidativedamage through the interplay of Prx2 and Nrf2 during stress erythropoiesis and suggest new therapeutic optionsto decrease ineffective erythropoiesis by modulation of endogenous antioxidant systems.