TY - JOUR
T1 - Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons
AU - Hervera, Arnau
AU - De Virgiliis, Francesco
AU - Palmisano, Ilaria
AU - Zhou, Luming
AU - Tantardini, Elena
AU - Kong, Guiping
AU - Hutson, Thomas
AU - Danzi, Matt C.
AU - Perry, Rotem Ben-Tov
AU - Santos, Celio X. C.
AU - Kapustin, Alexander N.
AU - Fleck, Roland A.
AU - Antonio Del Rio, Jose
AU - Carroll, Thomas
AU - Lemmon, Vance
AU - Bixby, John L.
AU - Shah, Ajay M.
AU - Fainzilber, Mike
AU - Di Giovanni, Simone
N1 - 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’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’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. A.H. performed and designed experiments, performed data analysis and wrote the manuscript; F.D.V. performed and designed experiments and performed data analysis; I.P. performed and designed experiments and performed data analysis; L.Z. performed experiments; E.T. performed experiments; G.K. performed experiments; T.H. performed experiments and edited the manuscript; M.C.D. performed data analysis; R.B.-T.P. performed experiments; C.X.C.S. performed experiments; A.N.K. designed experiments and provided technical support; R.A.F. designed experiments and provided technical support; J.A.D.R. supervised experiments and edited the manuscript; T.C. performed data analysis; V.L. supervised experiments and edited the manuscript; J.L.B. contributed to manuscript writing; A.M.S. supervised experiments and edited the manuscript; M.F. supervised experiments and edited the manuscript; S.D.G. designed experiments, performed data analysis and wrote the manuscript.
PY - 2018/3
Y1 - 2018/3
N2 - 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.Publisher correction: In the version of this Article originally published, the affiliations for Roland A. Fleck and José Antonio Del Río were incorrect due to a technical error that resulted in affiliations 8 and 9 being switched. The correct affiliations are: Roland A. Fleck: 8Centre for Ultrastructural Imaging, Kings College London, London, UK. José Antonio Del Río: 2Cellular and Molecular Neurobiotechnology, Institute for Bioengineering of Catalonia, Barcelona, Spain; 9Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; 10Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. This has now been amended in all online versions of the Article.
AB - 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.Publisher correction: In the version of this Article originally published, the affiliations for Roland A. Fleck and José Antonio Del Río were incorrect due to a technical error that resulted in affiliations 8 and 9 being switched. The correct affiliations are: Roland A. Fleck: 8Centre for Ultrastructural Imaging, Kings College London, London, UK. José Antonio Del Río: 2Cellular and Molecular Neurobiotechnology, Institute for Bioengineering of Catalonia, Barcelona, Spain; 9Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; 10Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. This has now been amended in all online versions of the Article.
UR - http://www.scopus.com/inward/record.url?scp=85041899028&partnerID=8YFLogxK
U2 - 10.1038/s41556-018-0039-x
DO - 10.1038/s41556-018-0039-x
M3 - مقالة
SN - 1465-7392
VL - 20
SP - 307
EP - 319
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 3
ER -