Nerves and hydrogen peroxide: how old enemies become new friends

Nerves and hydrogen peroxide: how old enemies become new friends

ROS and nerves play together during the regeneration process:For many years, the role of reactive oxygen species (ROS) in neurobiology has mainly focused on its pathological implications in neurodegenerative diseases. Contrasting with this view, ROS were recently put forward as key positive signals for axon growth and repair, highlighting beneficial functions of ROS signalling in the vertebrate adult brain (Borquez et al., 2016). Nerve injury is oen associated with damage of the neighbouring tissues. It was demonstrated, fi rst in larvae and then in adult vertebrates, that the increase of ROS production induced by tissue lesion stimulates axon growth (Rieger and Sagasti, 2011; Gauron et al., 2013; Meda et al., 2016). Tissue re-innervation, starting with axon regeneration, is a prerequisite to launch the regenerative program in damaged tissues and organs (Kumar and Brockes, 2012). As ROS are also required for regeneration to proceed (Gauron et al., 2013), simultaneous control of tissue and axon regeneration by a same redox signal would be a parsimonious way to coordinate the reformation of a fully functionaltissue (Meda et al., 2016) (Figure 1).

H2O2stimulates axon growth during development and adult regeneration:Appendage and organ regeneration are oen described as a replay of the developmental process.e role of hydrogen peroxide (H2O2) during morphogenesis was recently addressed in zebraf i sh thanks to the engineering of a transgenic fish line harbouring ubiquitous expression of the ratiometric HyPer sensor to monitor H2O2levelsin vivo. H2O2levels are highly dynamic, both spatially and temporally. They reach their maximum during early developmental stages, somitogenesis and organogenesis, and decrease at the end of morphogenesis down to minimal levels that persist in the adult. Within the embryo, the brain displays highest levels of H2O2. Soaking the embryos in a solution of NADPH oxidase pan-inhibitor (main enzymes responsible for H2O2production) dramatically reduces H2O2levels and impairs retinal ganglion cells axonal projections toward the tectum. Interestingly, this defect is rescued by either exogenous application of H2O2or activation of the Hedgehog pathway (Gauron et al., 2016).is situation is reminiscent of axonal growth during adult regeneration, which in the same way is controlled by the interplay between H2O2and Hedgehog (Meda et al., 2016) (Figure 2).

Figure 1 Nerves and hydrogen peroxide interact during regeneration and development.

Figure 2 Nerves, H2O2and Shh play together duringadult zebraf i sh fi n regeneration.

The identity of the targets of ROS signalling mediating axon regeneration remains an open question that, to be solved, will need to decipher the redox code of protein modif i cation (Jones and Sies, 2015). Cytoskeleton proteins, of which dynamic assembly is regulated by ROS signalling (Wilson and Gonzalez-Billault, 2015), are attractive candidates.

Nerves control H2O2levels:Since many decades, nerves were shown to be key players in metazoan regeneration and tissue repair. Back in the 1950’s, M. Singer proposed the existence of a neurotrophic factor, the “factor X”, produced by the nerves and diffusing in the damaged tissue, required to initiate and guide the progression of the regeneration process (Kumar and Brockes, 2012 and references therein). Recently, a denervation strategy in adult zebraf i sh has revealed that nerves control ROS levels both in physiological conditions and aer injury (Meda et al., 2016). In healthy tissues, nerves maintain low ROS levels thanks to Schwann cells, below the levels required for axon and organ regeneration (Meda et al., 2016). Aer amputation, injured nerves activate Shh signalling in Schwann cells that, in turn, is responsible for H2O2production in the wounded epidermis (Meda et al., 2016). It is tempting to propose that Shh might correspond to the “factor X” proposed by Singer in 1954, acting on H2O2production in the nerve regenerative environment.

Altogether, these fi ndings support the existence of a feedback loop between nerves and H2O2, in which nerves control H2O2levels in the tissue, which in turn participate in axon regrowth aer injury.ese data also lead us to propose that the redox environment of peripheral nerve endings might be a good target for the manipulation of adult cell plasticity (Figure 2).

Targeting nerves/redox levels loop in neurodegenerative diseases:Chronic wound and tumour irradiation are oen associated with neuropathies and in both cases, nerve degeneration is due to an inaccurate cross-talk between axon and glia (Zenker et al., 2013). Manipulation of Hedgehog signaling has been shown to reverse diabetic neuropathy (Calcutt et al., 2003), but only few reports have addressed the involvement of H2O2in this pathology (Pop-Busui et al., 2013; Papanas and Ziegler, 2014). Based on our recent fi ndings showing that the cross-talk between neurons and glia operating during vertebrate regeneration involves the combination of redox and Hedgehog signalling, we propose that interactions between these two pathways should be considered in other situations. In regenerative processes, although inf l ammation-induced ROS production could participate in axon recovery, the recent identif i cation of a feed-back loop between H2O2and axon growth might plead for more cautious approaches, due to the extreme sensitivity of nerves to ROS levels.

Francesca Meda, Alain Joliot, Sophie Vriz*

Centre Interdisciplinaire de Recherche en Biologie (CIRB), Collège de France, Paris, France (Meda F, Joliot A, Vriz S)

Université Paris Diderot, Sorbonne Paris Cité Biology Department, Paris, France (Vriz S)

PSL Research University, Paris, France (Meda F, Joliot A, Vriz S)

*Correspondence to:Sophie Vriz, Ph.D., vriz@univ-paris-diderot.fr.Accepted:2017-03-12

orcid:0000-0003-2029-5750 (Sophie Vriz)

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10.4103/1673-5374.205088

How to cite this article:Meda F, Joliot A, Vriz S (2017) Nerves and hydrogen peroxide: how old enemies become new friends. Neural Regen Res 12(4):568-569.

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