The Regents of the University of California (Irvine)
Hal X. Nyugen, Ph.D.
Post-doctoral Associate

Neutrophils Mediate Scar Formation/Cytogenesis after SCI

The central nervous system (CNS) is normally isolated and separated from the immune system by the blood brain/spinal barrier (BBB/BSB). However, disruption of the BBB/BSB as a result of traumatic injury permits the entrance of immune cells and other components of the immune system that can critically affect injury. Although macrophages and T-cells have been shown to affect injury, subsequent inflammation, scar formation, cytogenesis and neural regeneration, very little is known about the role of neutrophils or how they function to affect injury. As the first and most numerous cells to infiltrate the CNS after injury, neutrophils are most likely to exacerbate CNS injury and affect subsequent inflammation, scar formation, cytogenesis, and neural regeneration. Compared to other types of cells that infiltrate the CNS, neutrophils are known to release the highest levels of toxins such as free radicals, proteases, and pro-inflammatory cytokines that are elevated after CNS injury. Although damages to CNS tissue caused by free radicals, proteases, or cytokines have been reported, neutrophils have not previously been shown to affect neuronal cell death. In addition, the role of neutrophils in subsequent inflammation, scar formation, cytogenesis, and neural regeneration has not been previously investigated. Critically, the mechanisms of neutrophil function and the contribution of neutrophils to post-traumatic processes need to be investigated because (1) neutrophils may be an important mediator of CNS injury; and (2) clinical trials are currently proposed that may involve neutrophil depletion or recruitment inhibition. Today, most TBI and SCI patients have been living with paralysis for many years; therefore, the potential role of neutrophils to chronically affect cell death, scar formation, and cytogenesis would have critical relevance and may be helpful in the generation of effective therapeutic interventions for patients living with paralysis. We have shown in our cell culture experiments that neutrophils have the potential to promote neuronal cell death and affect post-injury processes such as scar formation or cytogenesis. We propose to extend and characterize these observations in mice after SCI through experiments utilizing a neutrophil antibody that depletes or neutralizes the number of neutrophils in mice. Our proposed investigations have critical relevance to paralysis because it may provide novel insight into a cytotoxic mechanism and a chronic role for neutrophils in scar formation/cytogenesis that may be helpful in the generation of effective therapeutic interventions for patients living with acute or chronic paralysis.