Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons

Arnau Hervera, Francesco De Virgiliis, Ilaria Palmisano, Luming Zhou, Elena Tantardini, Guiping Kong, Thomas Hutson, Matt C. Danzi, Rotem Ben Tov Perry, Celio X.C. Santos, Alexander N. Kapustin, Roland A. Fleck, José Antonio Del Río, Thomas Carroll, Vance Lemmon, John Bixby, Ajay M. Shah, Mike Fainzilber, Simone Di Giovanni

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis. Once in axonal endosomes, active NOX2 is retrogradely transported to the cell body through an importin-β1-dynein-dependent mechanism. Endosomal NOX2 oxidizes PTEN, which leads to its inactivation, thus stimulating PI3K-phosporylated (p-)Akt signalling and regenerative outgrowth. Challenging the view that ROS are exclusively involved in nerve degeneration, we propose a previously unrecognized role of ROS in mammalian axonal regeneration through a NOX2-PI3K-p-Akt signalling pathway.

Original languageEnglish (US)
Pages (from-to)307-319
Number of pages13
JournalNature Cell Biology
Volume20
Issue number3
DOIs
StatePublished - Mar 1 2018

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons'. Together they form a unique fingerprint.

  • Cite this

    Hervera, A., De Virgiliis, F., Palmisano, I., Zhou, L., Tantardini, E., Kong, G., Hutson, T., Danzi, M. C., Perry, R. B. T., Santos, C. X. C., Kapustin, A. N., Fleck, R. A., Del Río, J. A., Carroll, T., Lemmon, V., Bixby, J., Shah, A. M., Fainzilber, M., & Di Giovanni, S. (2018). Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. Nature Cell Biology, 20(3), 307-319. https://doi.org/10.1038/s41556-018-0039-x