Nerves Control Redox Levels in Mature Tissues Through Schwann Cells and Hedgehog Signaling

Aims: Recent advances in redox biology have emphasized the role of hydrogen peroxide (H(2)O(2)) in the modulation of signaling pathways and revealed that H(2)O(2) plays a role in cellular remodeling in adults. Thus, an understanding of the mechanisms that control H(2)O(2) levels in mature tissue would be of great interest. Results: We used a denervation strategy to demonstrate that sensory neurons are responsible for controlling H(2)O(2) levels under normal conditions and after being lesioned. Moreover, we demonstrate that severed nerves respond to appendage amputation via the induction of Hedgehog signaling and that this signaling is responsible for H(2)O(2) production in the wounded epidermis. Finally, we show that H(2)O(2) and nerve growth are regulated via reciprocal action in adults. Innovation and Conclusion: These data support a new paradigm for the regulation of tissue homeostasis: H(2)O(2) attracts nerves and nerves control H(2)O(2) levels in a positive feedback loop. This finding suggests that the peripheral nerve redox environment could be a target for manipulating cell plasticity in adults. Antioxid. Redox Signal. 24, 299–311.