Exosomal NADPH Oxidase: Delivering Redox Signaling for Healing

Lakshmi Krishnamoorthy†,§ and Christopher J. Chang*,†,§,‡,∥ †Department of Chemistry, University of California, Berkeley, California 94720, United States ‡Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, United States Howard Hughes Medical Institute, University of California, Berkeley, California 94720, United States Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, United States R oxygen species (ROS) make up a class of transient, redox-active small molecules that have long been studied for their deleterious effects in aging and disease progression. On the other hand, emerging data have revealed a more sophisticated biology for ROS, where regulated bursts of specific ROS like hydrogen peroxide (H2O2) that are generated by the NADPH oxidase (NOX) family of metalloproteins can trigger oxidative post-translational modifications at cysteines and methionines on target proteins to elicit downstream physiological responses. This signal/stress dichotomy is exquisitely illustrated in the brain, which consumes up to 20% of the oxygen taken up despite being only 2% of body weight, with aging and neurodegenerative disorders exhibiting strong connections to oxidative stress. A key feature of deciphering whether a particular ROS is a signal or stress agent in a given situation is the spatial and temporal nature of its production. In this context, a foundational physiological role for NOX-derived H2O2 signaling in the brain, as shown by two independent studies, is to maintain proliferation and neurogenic potential of neural stem cell populations. Indeed, stem cells derived from the two main neurogenic niches of the adult brain, the subventricular zone (SVZ) and the subgranular zone of the hippocampus, rely on regulated H2O2 production for proliferation and selfrenewal. Adult hippocampal progenitors produce H2O2 upon stimulation with growth factor via NOX2. Likewise, proliferating neural stem cells derived from the SVZ maintain a high level of ROS. Functional studies in NOX2 knockout and mutant mice show impaired proliferation and neurogenesis, establishing that redox-mediated regulation is critical for adult neurogenesis. Interestingly, these models share a common mechanism, in which the effects of H2O2 as an intracellular signal are mediated by oxidative inactivation of the phosphatase PTEN, which promotes phosphorylation of Akt and leads to enhanced survival and growth of these stem cells. An exciting study by Hervera et al. has expanded the scope of this biology to transcellular H2O2 signaling, reporting an essential role for H2O2 in axonal regeneration after an acute injury. A novel aspect of this system is that the injured neurons do not appear to generate H2O2 locally instead relying on recruited macrophages to deliver NOX2 and redox signaling through exosomes, which are then transported to the proper location to promote axonal growth (Figure 1). This finding is in line with previous observations that H2O2 can enhance axonal growth of sensory neurons after a skin injury in zebrafish models. Unlike the peripheral nervous system (PNS), central nervous system (CNS) neurons have limited abilities for regeneration after injury. One interesting mechanism by which CNS neurons can regenerate is described by the “conditioning lesion paradigm”. According to this concept, a prior lesion to the peripheral system can enhance central axon growth from a CNS injury that transpires at a later time point. The molecular players that mediate this recovery are insufficiently characterized but remain an attractive therapeutic avenue for stimulating regeneration after CNS injuries. Given that H2O2