A recent study published in Nature Neuroscience indicates that the increased susceptibility to life-threatening infections in spinal cord injury (SCI) patients may result from the disruption of the physiological interactions within a sympathetic-adrenal neuroimmune reflex – involving the sympathetic nervous system (SNS) and the adrenal glands.
Acute spinal cord injury causes systemic immunosuppression and life-threatening infections. Patients with spinal cord injury conditions are known to have increased occurrence of infections due to secondary neurally-induced immunosuppression.
The current view regards this immunosuppression as the result of SNS noradrenergic overactivation and the excessive release of glucocorticoids due to a dysregulated hypothalamus–pituitary–adrenal (HPA) axis. However, it is unknown whether these changes are due to humoral, via corticosteroids, or neural, via the SNS disruptions.
Recent reports delineated the role of secondary immune organs centering on the spleen. Despite responding to SCI with remarkable atrophy, blocked sympathetic signaling to the spleen was not able to reduce infection susceptibility to baseline levels after SCI, suggesting the existence of additional neurogenic pathomechanisms.
The authors of this study showed that high level (Th1) thoracic spinal cord transection decreased peripheral norepinephrine (noradrenaline) levels and increased corticosterone levels in mice without activating the HPA axis. In these animals, severe leukopenia, lymphoid organs atrophy, and spontaneous pneumonia developed. Moreover, SCI impaired thymic (T lymphocyte) and bone marrow (B lymphocyte) cell maturation and induced leukocyte apoptosis.
These post-SCI effects were inhibited by proper manipulation of the humoral or neural pathways. Adrenalectomy (ADX) or adrenal denervation (ANX) restored T and B-cell maturation and blood leukocyte count. Notably, ADX prevented lymphoid organ atrophy, and ANX animals did not develop pneumonia.
Thus, according to the authors, the “susceptibility to spontaneous pneumonia and severe lymphopenia after SCI resulted from a maladaptive sympathetic-neuroendocrine reflex involving the adrenal glands”. Importantly, they discuss that the sympathetic deafferentation of the adrenal gland contributed to the depletion of NE release from the adrenal medulla and the disinhibition of glucocorticoid release from the adrenal cortex, indicating a primary (i.e., adrenal) hypercortisolism.
The authors propose a two-step reflex mechanism where disruption of the tonic control of the adrenal glands by spinal cord efferents is followed by systemic effects that include low catecholamine levels and increased glucocorticoid release. These mechanisms have a major impact on lymphocyte maturation and migration, lymphoid organ development and cardiovascular alterations that may explain the immunosuppressive effects observed after SCI.