Incomplete Spinal Cord Injury Reverses the Level-Dependence of Spinal Cord Injury Immune Deficiency Syndrome

Abstract

Spinal cord injury (SCI) is associated with an increased susceptibility to infections, such as pneumonia, which is the leading cause of death in these patients. This phenomenon is referred to as SCI immune deficiency syndrome (SCI-IDS), and has been shown to be more prevalent after high-level transection in preclinical SCI models. Despite the high prevalence of contusion SCIs, the effects of this etiology have not been studied in the context of SCI-IDS. Compared to transection SCIs, which involve a complete loss of supraspinal input and lead to the disinhibition of spinally-generated activity, contusion SCIs may cause significant local deafferentation, but only a partial disruption of sympathetic tone below the level of injury. In this work, we investigate the effects of thoracic (T6-7) and cervical (C6-7) moderate–severe contusion SCIs on the spleen by characterizing splenic norepinephrine (NE) and cortisol (CORT), caspase-3, and multiple inflammation markers at 3- and 7-days post-SCI. In contrary to the literature, we observe an increase in splenic NE and CORT that correspond to an increase in caspase-3 after thoracic SCI relative to cervical SCI. Further, we found differences in expression of leptin, eotaxin, IP-10, and IL-18 that implicate alterations in splenocyte recruitment and function. These results suggest that incomplete SCI drastically alters the level-dependence of SCI-IDS.

Characterization of lumbar lymph node, a CNS-specific draining lymph node, after spinal cord injury in rats

“…Additionally, we found that in parallel to increased cell number in lumbar lymph node, the number of apoptotic cells also increased in lumbar lymph node on 7 days after injury. In agreement with our data, it has been recently demonstrated that thoracic spinal cord injury could enhance significantly apoptosis in spleen 3 and 7 days after thoracic spinal cord injury in rats [23,24]. Therefore, results obtained from the present study revealed a possible mechanism by which anatomical position and lymphatic pathways of CNS regional draining lymph nodes to the spinal cord could originate the differential immune response to spinal cord injury.…”

Splenic sympathetic signaling contributes to acute neutrophil infiltration of the injured spinal cord

“…2a). Previous studies have reported altered levels of NE in the spleen in response to SCI [2,5,13] weeks after the injury was performed. Here we show that increased levels of NE in the spleen can be detected as early as 1 dpi (t = 4.171; df = 6.134; p = 0.006) ( Fig.…”

“…Several systemic immune alterations have been documented after SCI. Studies demonstrate that SCI can promote proinflammatory responses damaging peripheral organs [28,29], to others showing deficient immune responses to pathogens or severe immunosuppression [1,[3][4][5]13].…”

“…SCI can severely impact spleen morphology and function although most alterations are documented at the chronic phase. Some of these include increased levels of norepinephrine (NE) [2,13], hyper sympathetic innervation [14], atrophy, and changes in immune cell frequencies [1,3,4]. The deregulation of the systemic immune response has been associated with overactive sympathetic signaling to lymphoid organs and to excessive activation of the hypothalamic-pituitary-adrenals axis (HPA).…”

Cytokine profile as a marker of cell damage and immune dysfunction after spinal cord injury

“…For instance, experiments in a rat model clearly demonstrated similar differences in the secretion of the vascular endothelial growth factor (VEGF), leptin, interferon-γ-induced chemokine IP- 10, IL-10, IL-18, the granulocyte colony-stimulating factor (G-CSF), and chemokine fractalkine in animals’ plasma. In contrast to the thoracic spine trauma, injury to the cervical spine is accompanied by a reduced expression of these mediators; this is probably due to sympathetic dysregulation, which is associated with higher injury severity [ 67 , 68 ]. Experiments on mice have also demonstrated that the involvement of the cytokine profile in the systemic changes of interleukins such as IL-3, IL-6, IL-10, IL-13, and G-CSF after a spinal cord injury to the lower thoracic region (Th910) is accompanied by the activation of T lymphocytes and neutrophils during the immediate post-traumatic phase of the observed changes [ 69 ].…”