Discovery of New Immune Cell Type May Unlock Strategies against Neurological Disorders and CNS Damage

Investigators at the Ohio State University Wexner Medical Center and the University of Michigan, have identified in mice a new type of immune cell, which their in vivo studies showed can rescue damaged nerve cells from death and partially reverse nerve fiber damage. The scientists also identified a human immune cell line that exhibits similar characteristics, and which promotes nervous system repair.

They suggest that the findings may point to new strategies for enabling recovery from degenerative neurological diseases, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), as well as from damage caused by traumatic brain and spine injuries and stroke. “This immune cell subset secretes growth factors that enhance the survival of nerve cells following traumatic injury to the central nervous system,” said Benjamin Segal, MD, professor and chair of the department of neurology at the Ohio State College of Medicine and co-director of the Ohio State Wexner Medical Center’s Neurological Institute. “It stimulates severed nerve fibers to regrow in the central nervous system, which is really unprecedented. In the future, this line of research might ultimately lead to the development of novel cell-based therapies that restore lost neurological functions across a range of conditions.”

Segal and colleagues reported on their studies in Nature Immunology, in a paper titled, “A new neutrophil subset promotes CNS neuron survival and axon regeneration.”

Neurons that are cut or severed typically don’t regenerate if they are in the central nervous system (CNS), which includes the retina, optic nerve, brain, brainstem, and spinal cord, the authors noted. “Axonal transection and neuronal death are pathological features of a wide range of CNS disorders, including traumatic brain or spinal cord injury (SCI), multiple sclerosis, and motor neuron disease.”

They are also hallmarks of glaucoma and ischemia-reperfusion injury of the eye, the scientists continued. There is therefore a “dire need” for novel therapies that might not only reduce, but potentially even reverse chronic neurological deficits. “One potential strategy that has been proposed to promote neuroprotection and regeneration involves modulation of the local immune response to CNS damage,” they noted.

Through their newly reported studies, in mice, Segal and colleagues discovered a new type of granulocyte cell, which they saw accumulated in the posterior chamber of the eye, in response to eye injury. Granulocytes are a type of white blood cell that contains small granules. The most common granulocytes, neutrophils, normally help the body to fight off infection. The newly identified, unique cell type resembles an immature neutrophil, but was found to have neuroprotective and neuroregenerative properties, and could drive central nervous system axon regrowth in the optic nerve, in vivo, in part through the secretion of a cocktail of growth factors. The same cell type was also capable of triggering axon regeneration in the spinal cord.

The researchers demonstrated the therapeutic power of the new immature neutrophil subset by injecting the cells into mice that had either crush injury to the optic nerve, or lacerated nerve fibers in the spinal cord. The experiments showed that animals receiving injections of this new neutrophil subset grew new nerve fibers, whereas animals given injections of more typical mature neutrophils, did not. “It doubles the number of surviving nerves, and it also stimulates a signifiant number of them to begin regenerating new fibers,” Segal said in a video interview.

“Our findings add to a growing body of literature that attests to the heterogeneity and functional subspecialization of circulating and tissue-infiltrating neutrophils,” the authors wrote. “In contrast to the widely held notion that myeloid cells that promote tissue repair are generally of the monocyte/macrophage lineage, the reparative cell that we characterize here is a CD14⁺Ly6G^lo granulocyte with features of an immature neutrophil …”

“We found that this pro-regenerative neutrophil promotes repair in the optic nerve and spinal cord, demonstrating its relevance across CNS compartments and neuronal populations,” commented first author Andrew Sas, MD, PhD, an assistant professor and physician scientist in the department of neurology at Ohio State. “A human cell line with characteristics of immature neutrophils also exhibited neuroregenerative capacity, suggesting that our observations might be translatable to the clinic.”

Segal, who is also director of Ohio State’s Neuroscience Research Institute, added, “I treat patients who have permanent neurological deficits, and they have to deal with debilitating symptoms every day. The possibility of reversing those deficits and improving the quality of life of individuals with neurological disorders is very exciting. There’s so much that we’re learning at the bench that has yet to be translated to the clinic, I think there’s huge potential for future medical breakthroughs in our field.”

The next step will be to harness this cell type and expand it in a lab to enhance its healing effects. Researchers hope the cells can then be injected into patients to improve function and mobility and slow or stop progressive neurological decline. “The distinctive mechanism of action of the Ly6Glo neuro-regenerative neutrophil subset makes it an attractive candidate for multimodal therapy, in synergy with agents that block cell-intrinsic or cell-extrinsic suppressors of axon growth, to rescue dying neurons and enhance axonal regeneration after CNS injury,” the team stated. Sas added, “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.”