Newly Discovered Neutrophils Promote Neuron Survival, Axon Regeneration

A newly recognized subset of neutrophils promotes neuron survival and axon regeneration in the central nervous system (CNS), researchers report.

"In previous studies of wound healing, subpopulations of monocytes have been implicated in repair," said Dr. Benjamin M. Segal of The Ohio State University Wexner Medical Center, in Columbus, and the University of Michigan, in Ann Arbor.

"It is extremely interesting that a cell of the neutrophil lineage acts in that capacity within the central nervous system, rescuing dying neurons and stimulating new nerve fiber growth," he told Reuters Health by email.

Immune-driven CNS axon regeneration following crushing injury to the murine optic nerve (a classic model) is enhanced by intraocular injection of zymosan, whose active ingredient is beta-1,3-glucan, which binds to the innate immune pattern recognition receptor dectin-1. The mediators that trigger neurorepair downstream of dectin-1 signaling are poorly understood.

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Dr. Segal and colleagues identified neutrophils as the predominant leukocyte subset in infiltrates following intraocular zymosan injection.

Treatment of zymosan-injected mice with CXCR2-blocking antiserum to impede the entry of mature neutrophils promoted the accumulation in the vitreous fluid of a subset of CD4+ granulocytes that expressed low levels of Ly6G.

These intraocular inflammatory cells, which had features of immature neutrophils, rescued retinal ganglion cells from cell death and stimulated axonal regeneration when transferred into the eyes of mice with optic-nerve crush injury, the researchers report in Nature Immunology.

Similarly, these low-Ly6G-expressing neutrophils facilitated axonal regeneration in injured mouse spinal cord.

These neutrophils were also shown to secrete growth factors that contribute to their neuroprotective and pro-regenerative functions, including nerve growth factor (NGF) and insulin-like growth factor 1 (IGF-1).

Neutralization of either of these factors (or both combined) inhibited neurite outgrowth of retinal ganglion cells in vitro.

Human myeloid cells with similar characteristics promoted axon regeneration, partly via an NGF/IGF-1-dependent pathway.

"The notion that inflammation only causes damage in the CNS is being overturned by research like our own," Dr. Segal said. "In unexpected ways, the immune system can actually promote neurorepair. The next challenge is to exploit these newly discovered neuroimmune pathways to restore lost functions in individuals with neurological conditions."

"These findings may lead to new cell-based therapies for a wide range of conditions characterized by neuronal cells loss and axonal damage, including traumatic brain and spinal cord injury, multiple sclerosis, glaucoma, and motor neuron disease," he said.

Dr. Segal added, "We are currently investigating protocols to differentiate pro-regenerative neutrophils from bone marrow cells in vitro, with the long-term goal of infusing those cells back into individuals with neurological damage. We are also identifying the combination of growth factors that are released by the neuroregenerative neutrophils to promote neurorepair, which could inform the development of a therapeutic cocktail."

The study did not have commercial funding, and the authors report no conflicts of interest.

—Will Boggs MD

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