The research team studied mice and found that damaged nerve cells produce a stream of molecular “lures” that specifically attract neutrophils to the injury sites. Once there, the neutrophils wrap around cellular debris caused by the nerve damage and clear the area so the cells can begin regenerating, much like clearing up debris after a tornado before repairs can begin.
Neutrophils are one of the most common types of immune cell – they are white blood cells that release enzymes during infections and allergic reactions, but have not been previously associated with nerve damage control.
The research team found that damaged sciatic nerves (the largest single nerve in the body) in the mouse models significantly produced more of two “chemoattractant” molecules (Cxcl1 and Cxcl2) which attach to the surfaces of neutrophils and lead them to the injured tissue. The cellular clearance mechanism is essential for the cells to properly regenerate.
“This finding is quite surprising and raises an important question: Do neutrophils play a significant role in nerve disorders?” said Richard Zigmond, Ph.D., professor of neurosciences, neurosurgery, and pathology at Case Western Reserve University School of Medicine, and senior author of the study.
A previous study with mice has attributed nerve damage control to another immune cell called macrophages as primarily responsible for engulfing and breaking down nerve debris. Specifically, the team studied genetically modified mice to lack a receptor on the surface of macrophages called CCR2, that helps these immune cells pinpoint injury sites. Zigmond asked his graduate student, Ph.D. candidate Jane Lindborg, to look for clearance of nerve cell debris in these mice.
“We expected that the clearance would be dramatically inhibited without the receptor. To our amazement, the clearance was unchanged from that in normal mice. The mystery Lindborg had to solve was how nerve cell debris is cleared in these mutant animals,” according to Zigmond.
In that previous study, the research team used several different tests to determine which cells were clearing away at the nerve debris after injury. “We came up with a list of potential cellular candidates that could be compensating for the loss of these specific macrophages,” Lindborg said. After hours of studying mouse cells, sorting immune cells found at injury sites by molecules on their cellular surfaces, the researchers found that it was the neutrophil that was a major contributor to debris removal. “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,” added Lindborg.
The team believes that their new findings could help design new therapeutics to help repair nerve cells damaged by neurodegenerative diseases such as Alzheimer's disease. “The clearance of debris after an injury is necessary to allow for effective nerve regeneration. Therefore, if one would want to enhance this clearance in patients, one would need to know what cells to target,” said Zigmond. (Related: New hope for Alzheimer's disease: Scientists find way to make brain-saving compound found in rare moss.)
The results also suggest that immunostimulant molecules – which are often used to treat chronic infections and immunodeficiencies – that target neutrophils at nerve injury sites might enhance clean-up and promote nerve cell regeneration, but it will need further studies to determine their specificity and effectiveness in the context of neuropathies, according to the researchers.
“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. We look forward to exploring exactly how these neutrophils work in concert with other cells to accomplish nerve regeneration,” said Lindborg.
The study was published in the Journal of Neuroscience.
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