FIG. 3.

NADPH oxidase signaling in the PNS under physiological conditions. Nox-derived ROS promote neurite outgrowth (A) and axon regeneration (B) under physiological conditions. (A) Nox2 and its cytosolic subunit p40^phox localize in growth cones, dynamic structures composed of an actin and microtubule cytoskeleton located at the tip of elongating neurites, which allows outgrowth and guidance to the proper target. Nox2-derived H₂O₂ oxidizes the actin cytoskeleton, changing its polymerization state and favoring neurite outgrowth (101). Nox2-derived H₂O₂ can also oxidize RyR localized in the ER, releasing Ca²⁺. This Ca²⁺-dependent process regulates different aspects of neurite outgrowth, including axonal development and polarization (144). (B) Following peripheral nerve lesion, macrophages release exosomal Nox2, which is taken up by injured axons via endocytosis and retrogradely transported to the cell body in an importin-β1–dynein-dependent mechanism. Endosomal Nox2 oxidizes PTEN, triggering a disulfide bond (SS) formation, which inactivates PTEN. PTEN inactivation favors PIP₂ phosphorylation (P) to PIP₃ and PI3K-Akt pathway activation, promoting nerve repair and axon regeneration (50). PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homologue; RyR, ryanodine receptors. Created with BioRender.com.