sTNF[alpha] Signaling Mediates Autonomic Reflex Circuits Implicated in Cardiovascular and Immune Dysfunction After Spinal Cord Injury

Abstract

The sympathetic nervous system is a critical regulator of cardiovascular and immune function. Sympathetic preganglionic neurons (SPN) reside in thoracolumbar cord and project peripherally to communicate information to vasculature and lymphoid organs. High-level spinal cord injury (SCI) can result in a loss of descending modulation of SPNs and lead to cardiovascular and immune dysfunction, which are two leading causes of mortality and morbidity after injury. Following SCI, SPNs become hyperactivated by autonomic reflexes in response to noxious stimuli below the level of the injury. Activation of these spinal sympathetic reflexes (SSR) can acutely manifest as autonomic dysreflexia (AD), a condition characterized by life-threatening hypertension in response to visceral or cutaneous stimuli. Recent work suggests that aberrant activity of this reflex can also suppress immune function. Furthermore, there are injury-induced changes to plasticity within the SSR circuits that further exacerbate sympathetic output and drive cardiovascular and immune dysfunction over time. Hyperexcitable circuits are a common sequela in other CNS disorders, including epilepsy and neuropathic pain. One commonality that may underlie these pathologies is an activated neuroimmune system. Interestingly, the pro-inflammatory, soluble form of the “master regulator” cytokine tumor necrosis factor [alpha] (sTNF[alpha]) has been shown to not only recruit immune cells to an injury site – sTNF[alpha] can also modulate neural circuits. Whether neuroinflammation instigates spinal plasticity related to the exacerbation of AD and dysimmunity has not been directly tested. We hypothesize that sustained sTNF[alpha]/TNFR1 signaling in the spinal cord below a SCI plays a crucial role in SSR circuit hyperactivity and consequent cardiovascular and immune dysfunction. In this thesis, we will assess whether pharmacologically inhibiting sTNF[alpha]/TNFR1 signaling attenuates these maladaptive changes. Results from chapter 2 demonstrate that immediate application of a sTNF[alpha] biologic, XPro1595, via continuous, intrathecal delivery below a thoracic segment 3 transection (T3Tx) can dramatically attenuate the development of naturally-occurring and induced AD as well as immunosuppression 4 weeks after SCI. Extracted mesenteric arteries from T3Tx-Saline animals exhibited increased sensitivity to vasopressors, suggestive of maladaptive vascular remodeling. Additionally, harvested spleens from T3Tx-Saline animals showed reduced levels of leukocytes suggestive of diminished immune function. Conversely, arteries from T3Tx-XPro1595 animals showed a normal pressor response and spleens from these animals also had normal leukocyte profiles Furthermore, XPro1595 animals show diminished intraspinal plasticity compared to T3Tx-Saline animals - far less activation of spinal interneurons in response following a colorectal stimulus, likely due to decreased arborization of colorectal nociceptive primary afferents. We believe that results from chapter 2 indicate that intrathecal XPro1595 may be a promising therapeutic strategy, so as a follow up study in chapter 3, we determined whether delaying initiation of XPro1595 at a more clinically relevant time point would sufficiently dampen SSRs, AD and improve dysimmunity. Indeed, delaying XPro1595 decreased recruitment of sympathetically-associated interneurons at both lumbar (where colorectal afferents synapse) and thoracic (locally to SPNs) levels compared to T3Tx-Saline animals. Likewise, T3Tx-XPro1595 animals had less naturally-occurring episodes of AD and diminished colorectal distension-induced AD over 8 weeks post-SCI. Interestingly, T3Tx-XPro1595 also fared much better than T3Tx-Saline animals following a bacterial infection 8 weeks after injury, suggestive of improved immunity. Collectively, the data presented in this thesis suggest that spinal inflammation may be a useful therapeutic target to curtail sympathetic reflexes implicated in secondary consequences of high-level SCI.Ph.D., Neuroscience -- Drexel University, 201