Neuronal adaptation to oxidative stress is crucial to prevent degenerative diseases. The role of the Nrf2/HO-1 system in cell response to hydrogen peroxide (H2O2) has been investigated using SH-SY5Y neuroblastoma cells as undifferentiated or after differentiation with all-trans retinoic acid (ATRA). We showed that undifferentiated cells resisted to oxidative stimulus and up-regulated HO-1 which was responsible for their survival, since its silencing decreased viability in cells exposed to H2O2. On the contrary, in ATRA-treated cells the viability decreased in response to increasing concentration of H2O2 and HO-1 was not induced. However, bilirubin supplementation restores cell viability, underlining the role of HO-1-derived bilirubin in cell resistance to oxidative stress. Investigating the mechanisms of HO-1 induction, we showed that in undifferentiated cells the nuclear level of Bach1, repressor of HO-1 transcription, decreased as well as its binding to the promoter of HO-1. In the same condition, Nrf2 binding to the same DNA region increased. Yet, in differentiated cells Bach1 nuclear level was not modified by the exposure to H2O2 as well as its binding to HO-1 promoter and, as a consequence, the binding of Nrf2 to HO-1 promoter was not modified by H2O2. In conclusion, our findings highlight the role of Bach1/HO-1/bilirubin in neuronal response to oxidative stress.
