A newly identified type of immune cell — a kind of immature neurophil or white blood cell — was found to be responsible for the regeneration and survival of eye and spinal cord nerve fibers that is known to be possible in mice with induced nerve injury, a study reported.
Its researchers suggest this finding may lead to immunotherapies capable of reversing nerve damage in people, and possibly restoring lost neurological function across a range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).
Their study, “A new neutrophil subset promotes CNS neuron survival and axon regeneration,” was published in the journal Nature Immunology.
The loss of nerve cells that control voluntary muscle movement (motor neurons) characterizes diseases like ALS, and current treatments generally aim to slow progression.
Ways of reversing neurological damage are being investigated. One proposed approach is to promote neuroprotection and regeneration by modulating local immune responses following nerve cell damage. Studies have shown that certain immune cells can be restorative in various neurological disorders.
Zymosan, a naturally occurring chemical, is also known to mitigate neuronal loss in mice and to rescue from death retinal ganglion cells (RGCs) — which give rise to optic (eye) nerve fibers — when injected after a crush injury to the optic nerve. It does so by inducing a kind of eye inflammation, but the exact cellular and molecular processes that trigger nerve cell repair are unknown.
Researchers at The Ohio State University Wexner Medical Center, with colleagues at the University of Michigan, gave zymosan injections to a mouse model of optic nerve crush injury to better study these processes.
First, cells from the animals’ eyes — collected over 14 days after optic nerve injury and injecting zymosan into the eye — found mostly immune cells known as neutrophils and macrophages, with neutrophils outnumbering all other immune cell subsets from days one to five.
The team identified a type of neutrophil that produced a protein called Ly6G, and with characteristics of immature neutrophils. When isolated five days after zymogen treatment, it directly stimulated the growth of primary RGCs in culture (a lab dish).
These immature neutrophils were found to be both activated in alternative ways and distinct from conventional or mature neutrophils, which normally secrete pro-inflammatory signaling proteins to fight infection.
To demonstrate these cells can induce neuroprotection and neuroregeneration, cells were also collected daily after zymogen injection into the abdomen of mice.
Cells isolated three days after injection were administered to the eyes of healthy mice with ocular nerve injury. This induced RGC survival and axonal regeneration, while cells isolated four hours after injection, which resembled mature neutrophils, were less effective.
Furthermore, cells administered after waiting six hours after ocular nerve injury triggered RGC axon regeneration, “demonstrating a therapeutic window that extends beyond the time of the acute traumatic event,” the researchers wrote.
While alternatively activated neutrophils are capable of promoting reparative functions in other immune cells, further experiments showed that these immature neutrophils could directly induce neuroprotective and neuroregenerative effects, and that their secreted proteins were the main participants in these processes.
Culturing the cells to find secreted proteins that promoted nerve regeneration identified two growth factors, known as nerve growth factor (NGF) and IGF-1. Both had highly elevated levels in cells three days after zymosan injection compared with four hours. These growth factors were also readily detectable in fluid within the eye on days three and five following zymosan injection.
Neutralizing either NGF or IGF-1 reduced LyG6 neutrophil-stimulated nerve regeneration, with the blocking of both growth factors together having a greater impact than blocking either one alone.
“This immune cell subset secretes growth factors that enhance the survival of nerve cells following traumatic injury to the central nervous system,” Benjamin Segal, MD, co-director of the Wexner Medical Center, said in a press release.
Significantly, LyG6 neutrophils on day three post-injection stimulated the growth of neurons isolated from spinal cords, whereas naive bone marrow neutrophils and four-hour LyG6 neutrophils were ineffective. Injecting three-day LyG6 cells five days before cutting sciatic nerve fibers in the spinal cord triggered regeneration.
“We found that this pro-regenerative neutrophil promotes repair in the optic nerve and spinal cord, demonstrating its relevance across [central nervous system] compartments and neuronal populations,” said Andrew Sas, MD, PhD, a neurologists and professor at Ohio State.
Finally, the team investigated whether a human immune cell type known as HL-60, which has characteristics of immature neutrophils, could initiate neuroregeneration. HL-60 cells stimulated the regrowth of severed RGC axons, while neutralizing NGF partially suppressed this effect.
“A human cell line with characteristics of immature neutrophils also exhibited neuro-regenerative capacity, suggesting that our observations might be translatable to the clinic,” Sas said. “Our findings could ultimately lead to the development of novel immunotherapies that reverse central nervous damage and restore lost neurological function across a spectrum of diseases.”
“I treat patients who have permanent neurological deficits, and they have to deal with debilitating symptoms every day,” Segal added. “The possibility of reversing those deficits and improving the quality of life of individuals with neurological disorders is very exciting.”
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