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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axons / enzymology*
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Axons / pathology
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CX3C Chemokine Receptor 1 / metabolism
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Cell Line
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Disease Models, Animal
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Dyneins / metabolism
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Endocytosis
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Endosomes / enzymology
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Endosomes / pathology
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Exosomes / enzymology*
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Exosomes / pathology
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Ganglia, Spinal / enzymology*
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Ganglia, Spinal / injuries
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Ganglia, Spinal / pathology
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Macrophages / enzymology
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Macrophages / pathology
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Mice, Inbred C57BL
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Mice, Knockout
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NADPH Oxidase 2 / deficiency
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NADPH Oxidase 2 / genetics
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NADPH Oxidase 2 / metabolism*
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Nerve Degeneration*
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Nerve Regeneration*
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Nuclear Proteins / metabolism
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PTEN Phosphohydrolase / metabolism
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Peripheral Nerve Injuries / enzymology*
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Peripheral Nerve Injuries / genetics
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Peripheral Nerve Injuries / pathology
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Peripheral Nerve Injuries / physiopathology
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Phosphatidylinositol 3-Kinase / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Reactive Oxygen Species / metabolism*
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Sciatic Nerve / enzymology*
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Sciatic Nerve / injuries
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Sciatic Nerve / pathology
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Sciatic Nerve / physiopathology
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Signal Transduction
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Spinal Cord Injuries / enzymology*
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Spinal Cord Injuries / genetics
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Spinal Cord Injuries / pathology
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Spinal Cord Injuries / physiopathology
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beta Karyopherins
Substances
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CX3C Chemokine Receptor 1
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Cx3cr1 protein, mouse
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Kpnb1 protein, mouse
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Nuclear Proteins
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Reactive Oxygen Species
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beta Karyopherins
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Cybb protein, mouse
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NADPH Oxidase 2
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Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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Pten protein, mouse
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Dyneins