Background: Synaptic plasticity helps in reducing the clinical expression of brain damage and represents a useful mechanism to compensate the negative impact of new brain lesions in multiple sclerosis (MS). Inflammation, altering synaptic plasticity, could negatively influence the disease course in relapsing-remitting MS (RR-MS). Objective: In the present study, we explored whether interleukin (IL)-6, a major proinflammatory cytokine involved in MS pathogenesis, alters synaptic plasticity and affects the ability to compensate for ongoing brain damage. Methods: The effect of IL-6 incubation on long-term potentiation (LTP) induction was explored in vitro, in mice hippocampal slices. We also explored the correlation between the cerebrospinal fluid (CSF) levels of this cytokine and the LTP-like effect induced by the paired associative stimulation (PAS) in a group of RR-MS patients. Finally, we examined the correlation between the CSF levels of IL-6 at the time of diagnosis and the prospective disease activity in a cohort of 150 RR-MS patients. Results: In vitro LTP induction was abolished by IL-6. Consistently, in patients with MS, a negative correlation emerged between IL-6 CSF concentrations and the effect of PAS. In MS patients, longer disease duration before diagnosis was associated with higher IL-6 CSF concentrations. In addition, elevated CSF levels of IL-6 were associated with greater clinical expression of new inflammatory brain lesions, unlike in patients with low or absent IL-6 concentrations, who had a better disease course. Conclusions: IL-6 interfering with synaptic plasticity mechanisms may impair the ability to compensate the clinical manifestation of new brain lesions in RR-MS patients.

中文翻译：

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Interleukin-6 破坏突触可塑性并损害多发性硬化症的组织损伤补偿

背景：突触可塑性有助于减少脑损伤的临床表现，并代表一种有用的机制来补偿多发性硬化症 (MS) 中新脑损伤的负面影响。炎症会改变突触可塑性，可能会对复发缓解型 MS (RR-MS) 的病程产生负面影响。目的：在本研究中，我们探讨了白细胞介素 (IL)-6（一种参与 MS 发病机制的主要促炎细胞因子）是否会改变突触可塑性并影响补偿持续脑损伤的能力。方法：在小鼠海马切片中体外探索了 IL-6 孵育对长时程增强 (LTP) 诱导的影响。我们还在一组 RR-MS 患者中探讨了这种细胞因子的脑脊液 (CSF) 水平与配对联想刺激 (PAS) 诱导的 LTP 样效应之间的相关性。最后，我们在 150 名 RR-MS 患者队列中检查了诊断时 IL-6 的 CSF 水平与预期疾病活动之间的相关性。结果： IL-6 消除了体外 LTP 诱导。一致地，在 MS 患者中，IL-6 CSF 浓度与 PAS 的作用之间出现负相关。在 MS 患者中，诊断前较长的病程与较高的 IL-6 CSF 浓度相关。此外，与 IL-6 浓度低或不存在的患者不同，脑脊液中 IL-6 水平升高与新发炎性脑病变的更大临床表现相关，谁有更好的病程。结论：IL-6 干扰突触可塑性机制可能会损害 RR-MS 患者新脑病变临床表现的代偿能力。