Long-term dynamics of the spinal cord injury neuroinflammatory response and sensory dysfunction in female mice
Neal J. Wrobel, Quan Shen, Dustin H. Kim, Bahar Adavoody, D A Prada, Richard G. Fessler, Brian T. David
Abstract
The neuroinflammatory response which takes place within the spinal cord following a traumatic spinal cord injury (SCI) is widely recognized as a major influencer of the progression and severity of the secondary tissue damage which occurs after injury onset. Immunomodulatory therapies aimed at reducing secondary injury are, therefore, a notable point of focus in SCI research. To inform future studies aimed at development of such therapies, we present a detailed characterization of the dynamics of the spinal cord neuroimmune response in mice throughout the first 6 months after contusive SCI. Female wild type (C57BL/6) mice received moderate spinal cord contusions at T9 (n = 8/cohort) while control mice remained naïve (n = 6/cohort). Nine terminal assessment time points were included, ranging from 1 day to 6 months post-injury (each timepoint was replicated between one and four times). At each terminal time point, levels of T cells, helper T cells, cytotoxic T cells, regulatory T cells, macrophages, and microglia within the spinal cord were assessed via flow cytometry. Measures of locomotor (open-field task) and sensory (tail flick) function were used to assess behavioral recovery. The spinal cord neuroimmune response in mice exhibited a biphasic pattern, with one peak of peripheral immune cell infiltration within the first 2 weeks post-injury, followed by a second peak at 2 months post-injury. Both T cells and macrophages remained elevated in injured spinal cords, relative to controls, at 6 months post-injury. Spinal cord inflammation correlated with exacerbated sensory impairment acutely but correlated with greater normalization of sensory function at 6 months post-injury. Higher inflammation at 6 months post-injury was also associated with an increase in spleen to body mass ratio. Together, the results of this investigation highlight the persistent nature of the SCI neuroinflammatory response and indicate that its relationship to other bodily systems continues to evolve even in the late-chronic stage of injury.