Spinal cord injury (SCI) disrupts critical physiological systems, including the cardiovascular and immune system. Plasticity of spinal circuits below the injury results in abnormal, heightened sympathetic responses, such as extreme, sudden
hypertension that hallmarks life-threatening
autonomic dysreflexia. Moreover, such sympathetic
hyperreflexia detrimentally impacts other effector organs, including the spleen, resulting in
spinal cord injury-induced immunodeficiency. Consequently,
infection is a leading cause of mortality after SCI. Unfortunately, there are no current treatments that prophylactically limit sympathetic
hyperreflexia to prevent subsequent effector organ dysfunction. The
cytokine soluble
tumor necrosis factor α (sTNFα) is upregulated in the CNS within minutes after SCI and remains elevated. Here, we report that commencing intrathecal administration of
XPro1595, an inhibitor of sTNFα, at a clinically feasible, postinjury time point (i.e., 3 d after complete SCI) sufficiently diminishes maladaptive plasticity within the spinal sympathetic reflex circuit. This results in less severe
autonomic dysreflexia, a real-time gauge of sympathetic
hyperreflexia, for months postinjury. Remarkably, delayed delivery of the sTNFα inhibitor prevents sympathetic
hyperreflexia-associated splenic
atrophy and loss of leukocytes to dramatically improve the endogenous ability of chronic SCI rats to fight off
pneumonia, a common cause of hospitalization after injury. The improved immune function with
XPro1595 correlates with less noradrenergic fiber sprouting and normalized
norepinephrine levels in the spleen, indicating that heightened, central sTNFα signaling drives peripheral,
norepinephrine-mediated organ dysfunction, a novel mechanism of action. Thus, our preclinical study supports intrathecally targeting sTNFα as a viable strategy to broadly attenuate sympathetic dysregulation, thereby improving cardiovascular regulation and immunity long after SCI.SIGNIFICANCE STATEMENT
Spinal cord injury (SCI) significantly disrupts immunity, thus increasing susceptibility to
infection, a leading cause of morbidity in those living with SCI. Here, we report that commencing intrathecal administration of an inhibitor of the proinflammatory
cytokine soluble
tumor necrosis factor α days after an injury sufficiently diminishes
autonomic dysreflexia, a real time gauge of sympathetic
hyperreflexia, to prevent associated splenic
atrophy. This dramatically improves the endogenous ability of chronically injured rats to fight off
pneumonia, a common cause of hospitalization. This preclinical study could have a significant impact for broadly improving quality of life of SCI individuals.