Functional Characterization of Nrf2 in erythroid cells: from erythropoiesis to mature red cells

Erythropoiesis is a dynamic and multistep process where early erythroid progenitors undergo differentiation into matured red cells. Nrf2 is a transcription factor that participates in acute response to oxidative stress and controls the expression of anti-oxidant and cytoprotective systems. Mice genetically lacking Nrf2 show a mild chronic hemolytic anemia due to erythrophagocytosis. Here, we show that Nrf2-/- mice display an age-dependent anemia characterized by accelerated senescence of circulating erythrocytes and reduced reticulocyte count, suggesting a perturbation of erythroid maturation process. Indeed, we found ineffective erythropoiesis in 12 months-old Nrf2-/- mice as supported by extramedullar erythropoiesis, increased ROS levels and cell apoptosis. In agreement, Nrf2-/- mice showed a blunted response to stress erythropoiesis induced by either PHZ or Doxo, suggesting an impairment of cellular back up mechanisms against oxidative stress such anti-oxidants and cytoprotective systems. The persistent oxidation promoted activation of UPR system and autophagy, which are unable to fully counteract oxidation re-directing cells towards apoptosis as supported by the increased caspase 3 activity. As a proof of concept, we used Astaxanthin as powerful anti-oxidant administrated in PLGA loaded nanoparticles (ATS-NP). In Nrf2-/- mice, ATS-NP ameliorated the age-dependent anemia and improved ineffective erythropoiesis with inactivation of UPR system and autophagy. In conclusion, we propose Nrf2 as key transcriptional factor against aged related oxidation to ensure erythroid maturation and growth. Future studies should be designed to evaluate the impact of Nrf2 activators as well as of ATS-NP administration in models of pathologic erythropoiesis.