Cell Surprise Prepares the Way for Nerve Regeneration

Wallerian degeneration. [Amrstrong Atlantic State University]

Studies by researchers in the U.S. have overturned previous models of how immune cells clear-up the debris associated with damaged peripheral nerve cells, suggesting potential new targets for promoting nerve regeneration. Prior models have assumed that macrophages take on this key job of removing debris around the sites of nerve cell damage. The new studies, headed Richard Zigmond, Ph.D., professor of neurosciences, neurosurgery, and pathology at Case Western Reserve University School of Medicine, suggest that it is neutrophils, and not macrophages, that carry out this clean-up role. “This finding is quite surprising and raises an important question: Do neutrophils play a significant role in nerve disorders?” Zigmond comments.

The studies are reported in the Journal of Neuroscience, in a paper entitled “Neutrophils Are Critical for Myelin Removal in a Peripheral Nerve Injury Model of Wallerian Degeneration.”

Peripheral nerve damage triggers a process known as Wallerian degeneration, which prepares the nerve cells for regeneration. Part of the process involves clearing up any debris around the site of damage. Previous models have assigned this clear-up job to chemokine CCR2 receptor-positive macrophages. However, studies by Dr. Zigmond’s lab showed that debris clear-up continues in mice that lacked the CCR2 receptor on their macrophages, and so can't recruit macrophages to the site of damage. “We expected that the clearance would be dramatically inhibited without the receptor, comments co-author, Jane Lindborg, who is a Ph.D. student in Zigmond’s lab. “To our amazement, the clearance was unchanged from that in normal mice.”

The researchers next had to figure out how the nerve cell debris was being cleared if not by macrophages. “We came up with a list of potential cellular candidates that could be compensating for the loss of these specific macrophages and used several different tests to determine which cells were clearing away the nerve debris after injury,” Lindborg continues. Their testing process involved sorting immune cells at injury sites according to cell-surface molecules, and also looking at cells under the microscope.

One of the observations was that damaged sciatic nerves in mice produced much greater than normal amounts of the the chemokines Cxcl1 and Cxcl2, which act as chemoattractants for neutrophils. It was these cells that the team confirmed were recruited to and cleared up the injury sites, and if neutrophils weren't present, there was a significant inhibition of nerve debris clearance. “Though it turns out that several different cells pick up the slack in the absence of macrophages, it was the neutrophil that emerged as a major contributor to debris removal,” Lindborg states. “We also discovered that when we depleted neutrophils, nerve debris clearance was significantly halted in both normal mice and mice lacking a major population of macrophages.”

The findings could feasbily lead to new therapeutic approaches that help to promote nerve cell repair, for example in neurodegenerative diseases. “The clearance of debris after an injury is necessary to allow for effective nerve regeneration,” Zigmond notes. Therefore, if one would want to enhance this clearance in patients, one would need to know what cells to target.” One potential approach would be the use of immunostimulants that target neutrophils to enhance debris clear-up around the damaged nerves and so promote regeneration.

“We have identified a novel and beneficial role for neutrophils in facilitating debris removal after injury, which has been shown to be an important step in promoting regeneration of the severed nerve, Lindborg concludes. “We look forward to exploring exactly how these neutrophils work in concert with other cells to accomplish nerve regeneration.”