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

摘要 患有慢性神经系统疾病的人，如脊髓损伤(SCI)， 有严重威胁生命的感染并发症的风险，包括甲型流感病毒(IAV)和肺炎。 感染是慢性脊髓损伤患者再次住院和死亡的主要原因。 因此，减少感染并发症对改善脊髓损伤的健康和寿命至关重要。 病人。 包括我们在内的几个小组一直在努力揭示脊髓损伤的潜在机制。 免疫性抑郁症。例如，上胸段(T3)脊髓损伤破坏了淋巴器官的交感神经调节。 并导致抗体合成障碍和脾细胞凋亡增加。上野的典雅书房和 同事们证明，高胸段脊髓损伤导致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招募， 从而提高了该电路的灵敏度。沉默这些谷氨酸能中间神经元恢复免疫 平衡，在没有病原体挑战的情况下，表明免疫平衡可以受到 神经发生机制。然而，病理可塑性的介质(S)和谷氨酸能中间神经元 脊髓损伤后激活尚未建立。我们有令人兴奋的初步数据表明，抑制 脊髓损伤后脊髓组织中的可溶性肿瘤坏死因子：减轻神经炎症和 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 (病毒载量减少，特异性CD8 T细胞增加)。 总体而言，这些数据为探索sTNF在脊髓损伤中的作用提供了强有力的科学前提。 导致免疫功能障碍。我们推测，脊髓中sTNF水平的升高 损伤在引发强大的神经炎症(例如，核因子-kB激活)和异常中起着关键作用 可塑性，继而导致脊髓损伤和外周免疫后交感神经回路的过度活跃 功能障碍。 这些重要的发现强调了局部sTNF信号在影响外周免疫中的作用。 根据这些数据，我们将在以下具体目标中： 目的1：确定神经元中sTNF/TNFR1信号在多大程度上促进免疫 脊髓损伤后的抑郁。 目的2：探讨sTNF在抗病毒免疫受损的外源性(外周)因素中的作用 慢性脊髓损伤小鼠的反应。

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.