@article{53548250975c446cb3bc7f985f52c630,
title = "Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons",
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.",
author = "Arnau Hervera and {De Virgiliis}, Francesco and Ilaria Palmisano and Luming Zhou and Elena Tantardini and Guiping Kong and Thomas Hutson and Danzi, {Matt C.} and Perry, {Rotem Ben Tov} and Santos, {Celio X.C.} and Kapustin, {Alexander N.} and Fleck, {Roland A.} and {Del R{\'i}o}, {Jos{\'e} Antonio} and Thomas Carroll and Vance Lemmon and Bixby, {John L.} and Shah, {Ajay M.} and Mike Fainzilber and {Di Giovanni}, Simone",
note = "Funding Information: We acknowledge financial support from the Leverhulme Trust (S.D.G.); the Hertie Foundation (S.D.G.); Wings for Life (S.D.G. and M.F.); the DFG (S.D.G.); start-up funds from the Division of Brain Sciences, Imperial College London (S.D.G.); the European Research Council (Neurogrowth, M.F.); Minerva Foundation (M.F.) and the Israel Science Foundation (M.F.); and the British Heart Foundation (A.M.S.). The research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (S.D.G.). M.F. is the incumbent of the Chaya Professorial Chair in Molecular Neuroscience at the Weizmann Institute of Science. We thank M. Malcangio and E. Old (King{\textquoteright}s College) for providing the Cx3cr1-null mice; W. M. Nauseef (University of Iowa) for critically discussing this manuscript; and G. Vizcay-Barrena at the Centre for Ultrastructural Imaging, King{\textquoteright}s College London for technical support. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = mar,
day = "1",
doi = "10.1038/s41556-018-0039-x",
language = "English (US)",
volume = "20",
pages = "307--319",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "3",
}