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 L Bixby; Ajay M Shah; Mike Fainzilber; Simone Di Giovanni

doi:10.1038/s41556-018-0039-x

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

Journal article

Peer reviewed

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, …

Nature cell biology, Vol.20(3), pp.307-319

2018-03

DOI: https://doi.org/10.1038/s41556-018-0039-x

PMID: 29434374

Abstract

Ganglia, Spinal - injuries

Sciatic Nerve - injuries

Axons - enzymology

Reactive Oxygen Species - metabolism

Exosomes - pathology

Sciatic Nerve - physiopathology

Spinal Cord Injuries - genetics

Spinal Cord Injuries - pathology

Endocytosis

CX3C Chemokine Receptor 1 - metabolism

Ganglia, Spinal - enzymology

Peripheral Nerve Injuries - physiopathology

Spinal Cord Injuries - enzymology

Proto-Oncogene Proteins c-akt - metabolism

Phosphatidylinositol 3-Kinase - metabolism

Disease Models, Animal

Dyneins - metabolism

Cell Line

NADPH Oxidase 2 - deficiency

Macrophages - pathology

Signal Transduction

Sciatic Nerve - pathology

Mice, Inbred C57BL

Peripheral Nerve Injuries - pathology

PTEN Phosphohydrolase - metabolism

Nuclear Proteins - metabolism

Endosomes - pathology

Nerve Regeneration

Macrophages - enzymology

Mice, Knockout

Animals

Peripheral Nerve Injuries - enzymology

NADPH Oxidase 2 - metabolism

Axons - pathology

Ganglia, Spinal - pathology

Exosomes - enzymology

Endosomes - enzymology

Spinal Cord Injuries - physiopathology

NADPH Oxidase 2 - genetics

Nerve Degeneration

Peripheral Nerve Injuries - genetics

Sciatic Nerve - enzymology

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.82 Gait & Posture; 1.82.875 Spinal Cord Injury
Web Of Science research areas: Cell Biology
ESI research areas: Molecular Biology & Genetics

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Title: Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons
Creators: Arnau Hervera - Cellular and Molecular Neurobiotechnology, Institute for Bioengineering of Catalonia, Barcelona, Spain
Francesco De Virgiliis - Graduate School for Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany
Ilaria Palmisano - Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
Luming Zhou - Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Elena Tantardini - Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
Guiping Kong - Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Thomas Hutson - Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
Matt C Danzi - The Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
Rotem Ben-Tov Perry - Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
Celio X C Santos - Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, UK
Alexander N Kapustin - Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, UK
Roland A Fleck - Centre for Ultrastructural Imaging, King's College London, London, UK
José Antonio Del Río - Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
Thomas Carroll - Bioinformatics Resource Centre, The Rockefeller University, New York, NY, USA
Vance Lemmon - The Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
John L Bixby - The Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
Ajay M Shah - Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, UK
Mike Fainzilber - Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
Simone Di Giovanni - 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
Publication Details: Nature cell biology, Vol.20(3), pp.307-319
Publisher: England
Grant note: RG/13/11/30384 / British Heart Foundation R01 HD057632 / NICHD NIH HHS PG/16/70/32310 / British Heart Foundation
Academic Unit: Leadership Department; Miller School of Medicine; Vice Provost for Research; John P. Hussman Institute for Human Genomics; Miami Project to Cure Paralysis; UMMG Dept of Neurological Surgery; Vice Provost for Research Administration
Language: English
Resource Type: Journal article
PMID: 29434374
Record Identifier: 991031577814302976