Schwann Cell Plasticity is Regulated by a Weakened Intrinsic Antioxidant Defense System in Acute Peripheral Nerve Injury

The biological effects of the transcription factor NF-E2-related factor 2 (Nrf2) in acute peripheral nervous system (PNS) injury have not been adequately elucidated. By analyzing the results of Nrf2 knockout and Nrf2 activation experiments, we found the following: (1) the antioxidant system was rapidly inactivated after acute PNS injury in a partly Nrf2-dependent manner, giving rise to a temporary state of oxidative stress, and then slowly and partially recovered following regeneration. (2) Nrf2 knockout promoted the reprogramming and proliferation of Schwann cells and inhibited myelination, as well as the redifferentiation of repair Schwann cells. (3) Dimethyl fumarate had no influence on the myelination of regenerated nerves. (4) Nrf2 functional regulation was able to regulate the redox status of nerves by changing the levels of target antioxidants and reactive oxygen species (ROS) at the same time, without altering the balance between them. In conclusion, the Nrf2-antioxidant system was temporarily inactivated in injured nerves, promoting Schwann cell reprogramming and proliferation, and its functional recovery was essential for Schwann cell redifferentiation and myelination.