Role of NF-kB in sympathetic hyperreflexia after spinal cord injury

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PROJECT SUMMARY / ABSTRACT Cardiovascular disease and immune dysfunction are the two leading causes of morbidity and mortality in individuals with high-level spinal cord injuries (SCI). This is primarily due to the development of sympathetic hyperreflexia, which is immediately apparent as an episode of autonomic dysreflexia (AD). AD is a condition occurring in up to 90% of patients with SCI above thoracic segment 6 that is characterized by life-threatening hypertension and reflexive bradycardia in response to below-level noxious sensory input. The frequency and severity of AD episodes progressively increase over time and contribute to increased risk for life-threatening infections, myocardial infarction, and stroke. The progressive exacerbation of sympathetic hyperreflexia is thought to be due to maladaptive plasticity within the spinal sympathetic reflex (SSR) circuit which contributes to heightened sensitivity and exaggerated sympathetic output to critical effector organs, such as vasculature and the spleen. This neurogenic sympathetic hyperreflexia thereby impairs peripheral immune function and contributes to systemic immunosuppression that further propagates infection susceptibility. Limiting SSR circuit plasticity and the development of sympathetic hyperreflexia could therefore have enormous therapeutic implications in mitigating injury-induced immunosuppression and greatly improve quality of life in individuals with SCI. Interestingly, the neuroimmune system is implicated as a major underling factor that contributes to the development of SSR circuit plasticity. Specifically, continued activation of resident microglia local and remote to the injury site is associated with the production of various proinflammatory cytokines, including soluble tumor necrosis factor-alpha (sTNFα), that are known to modulate neural circuits. Despite long-term inhibition of sTNFα after SCI, microglia continue to exhibit a reactive phenotype and there is persistent activation of NF-kB, a transcription factor complex that is activated by multiple cytokines, well below the SCI. This suggests that reactive microglia continue to produce a variety of cytokine factors in addition to sTNFα, which continue to activate NF- kB and thereby establish a pro-inflammatory autocrine loop. Furthermore, NF-kB has been implicated as a key mediator in chronic inflammatory disorders, such as rheumatoid arthritis, and directly contributes to synaptic and cellular plasticity. This proposal will focus on the hypothesis that activation of NF-kB after SCI contributes to driving SSR circuit plasticity that results in the development of sympathetic hyperreflexia and associated AD, as well as peripheral immune dysfunction. Moreover, we hypothesize that microglial NF-kB signaling alters neuronal excitability within the SSR circuit. The primary goals of this proposal are to: 1) investigate the role of NF-kB signaling in the development of sympathetic hyperreflexia (indicated by AD) and resultant dysimmunity (Aim 1); 2) elucidate how SCI-induced NF-kB activity in microglia shapes their phenotype and how that influences plasticity of neurons within the SSR circuit (Aim 2).