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

项目总结/摘要 心血管疾病和免疫功能障碍是发病率和死亡率的两个主要原因 脊髓损伤（SCI）的患者。这主要是由于交感神经系统的发展。 反射亢进，其立即表现为自主反射异常（AD）的发作。AD是一种条件 发生在高达90%的胸段6以上SCI患者中，其特征是危及生命 高血压和反射性心动过缓。的频率和 AD发作的严重程度随着时间的推移逐渐增加，并导致危及生命的风险增加， 感染、心肌梗塞和中风。交感神经反射亢进的进行性加重是 这被认为是由于脊髓交感神经反射（SSR）回路中的适应不良可塑性， 对关键效应器官（如脉管系统）的敏感性提高和交感神经输出增加， 脾脏这种神经源性交感神经反射亢进从而损害外周免疫功能， 有助于进一步传播感染易感性的全身免疫抑制。限幅SSR电路 因此，可塑性和交感神经反射亢进的发展可能具有巨大的治疗作用。 在减轻损伤诱导的免疫抑制和大大提高生活质量的个人与 SCI.有趣的是，神经免疫系统被认为是导致免疫缺陷的主要基础因素。 SSR电路可塑性的发展。具体来说，持续激活本地和远程的常驻小胶质细胞， 损伤部位与各种促炎细胞因子的产生有关，包括可溶性肿瘤细胞因子， 坏死因子-α（sTNFα），已知其调节神经回路。尽管长期抑制sTNFα SCI后，小胶质细胞继续表现出反应性表型，并且存在持续的NF-κ B活化， 转录因子复合物，由多种细胞因子激活，远低于SCI。这表明，反应性 除了sTNFα，小胶质细胞继续产生各种细胞因子，这些因子继续激活NF-κ B。 kB，从而建立促炎性自分泌回路。此外，NF-kB被认为是一个关键因素， 在慢性炎症性疾病如类风湿性关节炎中， 细胞可塑性该建议将集中在SCI后NF-κ B激活有助于 驱动SSR回路可塑性，导致交感神经反射亢进和相关AD的发展， 以及外周免疫功能障碍。此外，我们假设小胶质细胞NF-kB信号转导改变了神经元的 SSR电路内的兴奋性。本研究的主要目的是：1）研究NF-κ B的作用 交感神经反射亢进（由AD表示）和由此产生的免疫障碍（Aim 1）的发展中的信号传导; 2)阐明小胶质细胞中SCI诱导的NF-κ B活性如何塑造其表型，以及如何影响 SSR回路内神经元的可塑性（目的2）。

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).