Newly Discovered Neutrophil Subset Reverses Permanent CNS Damage

Super-resolution fluorescence microscopy image of neurons.
Super-resolution fluorescence microscopy image of neurons (blue) showing the actin cytoskeleton (red) and the tips of the microtubule cytoskeleton (green). Source: NIH (Ian Hutchins and Susan Wray)

Severe damage to the axons of nerves within the brain and spinal cord, such as following a stroke or motor vehicle accident, frequently does not heal well and is an important source of long-term neurologic disability in the United States. It is estimated that 288,000 Americans live with spinal cord injury, and millions present to the emergency department with traumatic brain injuries each year.

While therapies are available that alleviate the symptoms of neurological damage, there are currently no effective methods for reversing permanent central nervous system (CNS) damage and restoring patients to full health. However, recent research suggests that this may one day change, and that the immune system could play an integral role.

Researchers from The Ohio State University and the University of Michigan have identified a unique subset of white blood cell that directly fosters the regeneration of nerve axons within the CNS. Their discovery, published in the journal Nature Immunology, has important implications for patients suffering from neurological damage as it could eventually lead to the development of novel immune-based therapies that repair damaged structures within the brain or spinal cord.

“As a practicing neurologist I am acutely aware of the challenges faced by people with neurological disease and chronic deficits,” senior author Dr. Benjamin Segal told ImmunoFrontiers. “Although great strides have been made in alleviating neurological symptoms across a spectrum of diseases and, in some cases, in preventing or mitigating neurological damage, little progress has been made in the development of therapies that restore lost neurological functions.”

“Therefore, when my lab learned about a mouse model of immune driven nerve fiber (axon) regeneration, we decided to investigate the underlying mechanisms and, ultimately, to explore potential therapeutic applications.”

“In that model, the induction of inflammation in the posterior chamber of the eye via intraocular injection of fungal cell wall extract (zymosan) is associated with the regeneration of severed optic nerve axons and enhanced survival of retinal ganglion cells (the neurons that give rise to optic nerve axons). We hypothesized that a subpopulation of innate immune cells possess neuroprotective and neuroregenerative properties.”

“We analyzed the immune cells that accumulate in the eye, in response to intraocular administration of zymosan, via flow cytometry, transcriptomic profiling (including single cell RNAseq), cytospin, and neurite outgrowth assays. These studies led to the identification of a subset of myeloid cells, with features of immature neutrophils, that produce an array of growth factors and directly stimulate nerve fiber outgrowth upon co-culture with explanted neurons isolated from different sites in the central nervous system. These immature neutrophils express markers similar to those of “alternatively activated” macrophages previously implicated in peripheral wound healing.”

“Adoptive transfer of zymosan-induced immature neutrophils, into the posterior chamber of the eye of mice with optic nerve crush injury, rescued dying neurons and stimulated axonal regrowth in vivo. These cells were also effective in inducing axon regeneration in the spinal cord. Similarly, a human cell line with characteristics of immature neutrophils stimulated neurite outgrowth of explanted human cortical neurons in vitro and of severed optic nerve axons in immunodeficient mice in vivo.”

“Our study identifies a new myeloid cell phenotype with neuroprotective and axogenic properties that arises in the setting of optic nerve and spinal cord injury. This research may ultimately lead to the develop of an infusable cellular therapy, or drugs that promote the development and expansion of endogenous populations of neuroprotective/neuroregenerative immune cells, to reverse neurological deficits in individuals with neurological damage or neurodegenerative diseases.”

Their study, “A new neutrophil subset promotes CNS neuron survival and axon regeneration,” was published in the journal Nature Immunology and represents only the start of their journey to better-characterize this exciting new cell type.

Moving forwards, the team plans to expand their research and investigate the molecular mechanisms governing the behavior of these cells more closely, among other pursuits.

“We are interrogating the pathways that drive the polarization of neurorestorative neutrophils and/or their migration to sites of nervous system injury in vivo. We are also assessing the therapeutic potential of those cells in models of a spectrum of different neurological disorders.  Finally, we are searching for the endogenous human counterpart of the murine neurorestorative myeloid cell subset.”

Dr. Segal’s take-home message for readers: “There is a pressing, unmet need to restore lost neurological functions in people with traumatic brain and spinal cord injury, stroke, multiple sclerosis and a range of other neurological conditions. Our study suggests that immunomodulatory strategies should be explored as a potential approach to repair the damaged nervous system.”

Read more about the latest research in the field of immunology.

Sas, A.R., Carbajal, K.S., Jerome, A.D. et al. A new neutrophil subset promotes CNS neuron survival and axon regeneration. Nat Immunol 21, 1496–1505 (2020). https://doi.org/10.1038/s41590-020-00813-0