Traumatic injury to the brain and spinal cord is responsible for significant morbidity and mortality among accident victims, military personnel engaged in active combat, and athletes at risk of concussion. Poor clinical outcomes are due, in large part, to the limited regenerative capacity of severed axons to regrow in the central nervous system (CNS). Accumulating evidence points to “alternatively activated” immune cells and their factors as promising therapeutic targets for facilitating neurorepair. Intraocular (i.o.) inflammation, induced by the local application of zymosan, a fungal cell wall extract, drives robust re-growth of transected retinal ganglion cell (RGC) axons following optic nerve crush (ONC) injury in adult mice. The identity of the neuroregenerative inflammatory cells in this model, and the conditions necessary for their differentiation, are poorly understood. We found thatLy6G+ neutrophils are the predominantconstituent of zymosan-elicited i.o. infiltrates. Furthermore, we identified a novel subset of Ly6Glow CD14+ neutrophils in the infiltrates that correlate with the extent of RGC axon regeneration. Ly6GlowCD14+ neutrophils, or their CM, directly stimulated RGC neurite outgrowth in vitro. The pro-regenerative properties of the CM was abrogated by heat shock. Protein analysis indicated that Ly6GlowCD14+ neutrophils produce numerous growth factors that can stimulate axon regrowth after transection including nerve growth factor (NGF) and insulin like growth factor-1 (IGF1). Ly6Glow neutrophils adoptively transferred into the eye after ONC directly stimulated axon regeneration in vivo, and this effect was attenuated with blockade of NGF or IGF-1. Our studies may ultimately lead to the development of novel immunomodulatory drugs, or the repurposing of immunomodulatory drugs already in clinical use, to promote the differentiation and expansion of neuroregenerative neutrophils in patients with traumatic CNS injury or other disorders characterized by axonopathy.
Friday, October 19, 2018
Dr. Andrew Sas, Assistant Professor, University of Michigan Department of Neurology, presents the Neurology/Neuroscience Research Seminar this Friday, October 19th at Noon
12:00 PM to 1:00 PM
Room 5515 Biomedical Science Research Building (BSRB), 109 Zina Pitcher Place, Ann Arbor, MI 48109
Neutrophil Driven Axon Regeneration