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Nat Cell Biol. 2018 Mar;20(3):307-319. doi: 10.1038/s41556-018-0039-x. Epub 2018 Feb 12.

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

Author information

1
Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
2
Cellular and Molecular Neurobiotechnology, Institute for Bioengineering of Catalonia, Barcelona, Spain.
3
Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
4
Graduate School for Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany.
5
The Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.
6
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
7
Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, UK.
8
Centre for Ultrastructural Imaging, King's College London, London, UK.
9
Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
10
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
11
Bioinformatics Resource Centre, The Rockefeller University, New York, NY, USA.
12
Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK. s.di-giovanni@imperial.ac.uk.
13
Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. s.di-giovanni@imperial.ac.uk.

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.

PMID:
29434374
DOI:
10.1038/s41556-018-0039-x
[Indexed for MEDLINE]

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