Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality. Since bone marrow hematopoiesis is essential for proper immune function, we hypothesize that SCI disrupts bone marrow hematopoiesis. Indeed, SCI causes excessive proliferation of bone marrow hematopoietic stem and progenitor cells (HSPC), but these cells cannot leave the bone marrow, even after challenging the host with a potent inflammatory stimulus. Sequestration of HSPCs in bone marrow after SCI is linked to aberrant chemotactic signaling that can be reversed by post-injury injections of Plerixafor (AMD3100), a small molecule inhibitor of CXCR4. Even though Plerixafor liberates HSPCs and mature immune cells from bone marrow, competitive repopulation assays show that the intrinsic long-term functional capacity of HSPCs is still impaired in SCI mice. Together, our data suggest that SCI causes an acquired bone marrow failure syndrome that may contribute to chronic immune dysfunction.

Mouse models have provided key insight into the cellular and molecular control of human immune system function. However, recent data indicate that extrapolating the functional capabilities of the murine immune system into humans can be misleading. Since immune cells significantly affect neuron survival and axon growth and also are required to defend the body against infection, it is important to determine the pathophysiological significance of spinal cord injury (SCI)-induced changes in human immune system function. Research projects using monkeys or humans would be ideal; however, logistical and ethical barriers preclude detailed mechanistic studies in either species. Humanized mice, i.e., immunocompromised mice reconstituted with human immune cells, can help overcome these barriers and can be applied in various experimental conditions that are of interest to the SCI community. Specifically, newborn NOD-SCID-IL2rgnull (NSG) mice engrafted with human CD34+ hematopoietic stem cells develop normally without neurological impairment. In this report, new data show that when mice with human immune systems receive a clinically-relevant spinal contusion injury, spontaneous functional recovery is indistinguishable from that achieved after SCI using conventional inbred mouse strains. Moreover, using routine immunohistochemical and flow cytometry techniques, one can easily phenotype circulating human immune cells and document the composition and distribution of these cells in the injured spinal cord. Lesion pathology in humanized mice is typical of mouse contusion injuries, producing a centralized lesion epicenter that becomes occupied by phagocytic macrophages and lymphocytes and enclosed by a dense astrocytic scar. Specific human immune cell types, including three distinct subsets of human monocytes, were readily detected in blood, spleen and liver. Future studies that aim to understand the functional consequences of manipulating the neuro-immune axis after SCI should consider using the humanized mouse model. Humanized mice represent a powerful tool for improving the translational value of pre-clinical SCI data.

People who suffer a traumatic spinal cord injury (SCI) are at increased risk for developing dermatological complications. These conditions increase cost of care, incidence of rehospitalization, and the risk for developing other infections. The consequences of dermatological complications after SCI are likely exacerbated further by post-injury deficits in neural-immune signaling. Indeed, a functional immune system is essential for optimal host defense and tissue repair. Here, we tested the hypothesis that SCI at high spinal levels, which causes systemic immune suppression, would suppress cutaneous inflammation below the level of injury. C57BL/6 mice received an SCI (T3 spinal level) or sham injury; then one day later complete Freund's adjuvant (CFA) was injected subcutaneously below the injury level. Inflammation was quantified by injecting mice with V-Sense, a perfluorocarbon (PFC) tracer that selectively labels macrophages, followed by in vivo imaging. The total radiant efficiency, which is proportional to the number of macrophages, was measured over a 4-day period at the site of CFA injection. Fluorescent in vivo imaging revealed that throughout the analysis period, the macrophage reaction in SCI mice was reduced ∼50% compared with sham-injured mice. Radiant efficiency data were confirmed using magnetic resonance imaging (MRI), and together the data indicate that SCI significantly impairs subcutaneous inflammation. Future studies should determine whether enhancing local inflammation or boosting systemic immune function can improve the rate or efficiency of cutaneous wound healing in individuals with SCI. Doing so also could limit wound infections or secondary complications of impaired healing after SCI.

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