Arnau Hervera and José Antonio del Río
which sends macrophages – immune cells typically associated with inflammatory processes – to clean up the damaged area. In addition, high levels of oxidation (or ‘reactive oxygen species’ (ROS) – chemicals such as peroxides that inevitably form during an organism’s metabolism of oxygen – occur. These damage the membrane and DNA of some neurons, and even cause the death of some cells.
Although you’d think that inhibiting the inflammatory response and oxidation after injury would avoid this damage, researchers from the Institute of Bioengineering of Catalonia (IBEC) and Imperial College have discovered that oxidation can actually promote the regeneration of axons after a nerve injury.
Dr. Arnau Hervera, first author of the study, and Prof. José Antonio del Río, both at IBEC, in collaboration with the laboratory of Prof. Simone Di Giovanni at Imperial College, investigated the mechanism that mediates regeneration after spinal cord injuries. To do this, they first subjected animals to ‘conditioning nerve lesions’, known since the 1970s for their contribution to regeneration in later lesions, but whose mechanisms have not yet been clarified. “When there’s a prior, smaller injury to the nervous system, recovery after an acute injury is more effective,” says Dr. Hervera. “It’s a mechanism like a vaccine, preparing the immune system for a possible attack: cellular memory, in other words.”
The researchers concentrated on understanding the mechanism behind the first injury. “We realized that the ROS always accompanied regeneration when a prior injury had occurred. For this reason, we decided to simulate this conditional injury by simply releasing the ROS near the damaged area,” says Dr. Hervera.
To do this, they administered a type of ROS – oxygenated water – in the sciatic nerve. Four weeks after a spinal cord injury, only the animals that had received the injection of ROS were functional again. “A conditional lesion would never be of therapeutic use, but if we understand the mechanisms behind it – basically, how this oxidation works – we could control and improve regeneration after spinal cord injuries,” says Prof. del Río, principal investigator at IBEC and at the University of Barcelona’s Institute of Neurosciences, as well as professor at the university.
In their search for the mechanism responsible for this oxidation via the ROS, the researchers identified macrophages as responsible for the signaling required by ROS in damaged neurons to promote the regeneration of injured axons.
The discovery could inspire the creation of new regenerative therapies that promote recovery after nerve or spinal cord injury by regulating ROS signaling. “The solution would be to modulate the oxidant and inflammatory response of the body instead of blocking it, as we currently do,” says Dr. Hervera. “It questions the use of antioxidant and anti-inflammatory therapies for nerve injuries, as it is evidence of the need to have an immune response that participates in the regeneration process.”
The research was funded by the Leverhulme Trust, Wings for Life and Imperial College London.
Reference article: A. Hervera, F. De Virgiliis, I. Palmisano, L. Zhou, E. Tantardini, G. Kong, T. Hutson, M. C. Danzi, R. Ben-Tov Perry, C. X. C. Santos, A. N. Kapustin, R. A. Fleck, J. A. Del Río, T. Carroll, V. Lemmon, J. L. Bixby, A. M. Shah, M. Fainzilber and S. Di Giovanni (2018). Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH2 oxidase complexes into injured axons. Nature Cell Biology, pub ahead of print.
