SCI-induced deficits in antiviral immunity: The role of sTNF.

摘要 患有慢性神经系统疾病（例如脊髓损伤（SCI））的个体，患病率更高 感染导致严重危及生命的并发症的风险，包括甲型流感病毒 (IAV) 和肺炎。 感染是慢性 SCI 患者再住院和死亡的主要原因。 因此，减少感染并发症对于改善 SCI 的健康和寿命至关重要 患者。 包括我们在内的几个研究小组一直致力于揭示 SCI 诱发的潜在机制。 免疫抑制。例如，高位胸部 (T3) SCI 会破坏淋巴器官的交感神经调节 并导致抗体合成受损和脾细胞凋亡增加。上野和的优雅研究 同事们证明，高位胸部 SCI 引起的免疫功能障碍在很大程度上是由于大量的 脊髓交感神经反射回路的重组，例如谷氨酸能中间神经元的募集， 导致该电路的灵敏度增加。沉默这些谷氨酸能中间神经元可以恢复免疫 平衡，在没有病原体攻击的情况下，证明免疫平衡可能受到以下因素的影响 神经源性机制。然而，病理可塑性和谷氨酸能中间神经元的介质 SCI 后的激活尚未确定。我们有令人兴奋的初步数据表明抑制 SCI 后脊髓中的可溶性肿瘤坏死因子 (sTNF)：减轻神经炎症， 异常的神经元可塑性和激活，减少免疫功能障碍，提高抗病毒免疫力 （病毒载量减少，特异性 CD8 T 细胞增加）。 总的来说，这些数据为探索 sTNF 在 SCI 中的作用提供了强有力的科学前提。 诱发免疫功能失调。我们假设脊髓中 sTNF 水平升高后 损伤在引发强烈的神经炎症（例如 NF-kB 激活）和异常方面发挥着至关重要的作用 可塑性反过来导致 SCI 和外周免疫后交感神经回路过度活跃 功能障碍。 这些重要的发现强调了局部 sTNF 信号传导在影响外周免疫方面的作用。 基于这些数据，我们将实现以下具体目标： 目标 1：确定神经元中 sTNF/TNFR1 信号传导对免疫的贡献程度 SCI 后抑郁症。 目标 2：研究 sTNF 对抗病毒免疫受损的外在（外周）因素的影响 慢性 SCI 小鼠的反应。

Abstract Individuals suffering from chronic neurological disorders, such as spinal cord injury (SCI), are at greater risk of serious life-threatening complications from infections, including Influenza A virus (IAV) and pneumonia. Infections are the leading cause of re-hospitalization and mortality in patients living with chronic SCI. Therefore, reducing complications from infections is critical for improving the health and life span of SCI patients. Several groups, including ours, have endeavored to uncover the mechanisms underlying SCI-induced immune depression. For example, high-thoracic (T3) SCI disrupts sympathetic regulation of lymphoid organs and leads to impaired antibody synthesis and increased splenocyte apoptosis. Elegant studies by Ueno and colleagues demonstrated that high-thoracic SCI-induced immune dysfunction is due, in large part, to massive reorganization of the spinal sympathetic reflex circuit, e.g. the recruitment of glutamatergic interneurons, that results in increased sensitivity of this circuit. Silencing these glutamatergic interneurons restored immune balance, in the absence of pathogen challenge, demonstrating that immune balance can be affected by neurogenic mechanisms. However, the mediator(s) of pathological plasticity and glutamatergic interneuron activation post-SCI have not been established. We have exciting preliminary data suggesting that inhibiting soluble Tumor Necrosis Factor (sTNF) in the spinal cord following SCI: attenuates neuroinflammation and aberrant neuronal plasticity and activation, reduces immune dysfunction, and improves antiviral immunity (reduced viral load, increased specific CD8 T cells). Collectively, these data provide for a strong scientific premise to explore the role of sTNF in SCI- induced immune dysfunction. We hypothesize that heightened levels of sTNF in the spinal cord after injury play a crucial role in triggering robust neuroinflammation (e.g., NF-kB activation) and aberrant plasticity that, in turn, lead to hyperactivity of sympathetic circuitry after SCI and peripheral immune dysfunction. These important findings highlight the role of local sTNF signaling in influencing peripheral immunity. Based upon these data, in the following specific aims, we will: Aim 1: Determine the extent that sTNF/TNFR1 signaling in neurons contributes to immune depression following SCI. Aim 2: Investigate the contribution of sTNF to extrinsic (peripheral) factors of impaired antiviral immune responses in chronic SCI mice.