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Abstract：
BACKGROUND: Multiple sclerosis (MS) is a progressive neurodegenerative disease of the central nervous system characterized by inflammation-driven synaptic abnormalities. Interleukin-9 (IL-9) is emerging as a pleiotropic cytokine involved in MS pathophysiology.
METHODS: Through biochemical, immunohistochemical, and electrophysiological experiments, we investigated the effects of both peripheral and central administration of IL-9 on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS.
RESULTS: We demonstrated that both systemic and local administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in EAE. The results unveil an unrecognized central effect of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity by enhancing the expression of the triggering receptor expressed on myeloid cells-2 (TREM2) and reducing TNF release. Second, IL-9 suppressed neuronal TNF signaling, thereby blocking its synaptotoxic effects.
CONCLUSIONS: The data presented in this work highlight IL-9 as a critical neuroprotective molecule capable of interfering with inflammatory synaptopathy in EAE. These findings open new avenues for treatments targeting the neurodegenerative damage associated with MS, as well as other inflammatory and neurodegenerative disorders of the central nervous system.
METHODS: Through biochemical, immunohistochemical, and electrophysiological experiments, we investigated the effects of both peripheral and central administration of IL-9 on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS.
RESULTS: We demonstrated that both systemic and local administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in EAE. The results unveil an unrecognized central effect of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity by enhancing the expression of the triggering receptor expressed on myeloid cells-2 (TREM2) and reducing TNF release. Second, IL-9 suppressed neuronal TNF signaling, thereby blocking its synaptotoxic effects.
CONCLUSIONS: The data presented in this work highlight IL-9 as a critical neuroprotective molecule capable of interfering with inflammatory synaptopathy in EAE. These findings open new avenues for treatments targeting the neurodegenerative damage associated with MS, as well as other inflammatory and neurodegenerative disorders of the central nervous system.
摘要：
背景：多发性硬化（MS）是中枢神经系统的进行性神经退行性疾病，其特征是炎症驱动的突触异常。白细胞介素-9（IL-9）是一种参与MS病理生理学的多效性细胞因子。
方法：通过生化，免疫组织化学，和电生理实验，我们研究了外周和中枢给药IL-9对C57/BL6雌性小鼠实验性自身免疫性脑脊髓炎（EAE）的影响，女士的模型
结果：我们证明，全身和局部给药IL-9可显著改善临床残疾，减少神经炎症，减轻EAE中的突触损伤。结果揭示了IL-9对抗小胶质细胞和TNF介导的神经元兴奋性毒性的未识别的中枢作用。出现了两个主要机制:第一，IL-9通过增强在骨髓细胞-2（TREM2）上表达的触发受体的表达和减少TNF释放来调节小胶质细胞的炎症活性。第二,IL-9抑制神经元TNF信号,从而阻断其突触毒性作用。
结论：这项工作中提供的数据强调了IL-9作为一种关键的神经保护分子，能够干扰EAE中的炎性突触病。这些发现为针对与MS相关的神经退行性损伤的治疗开辟了新的途径。以及中枢神经系统的其他炎症和神经退行性疾病。
方法：通过生化，免疫组织化学，和电生理实验，我们研究了外周和中枢给药IL-9对C57/BL6雌性小鼠实验性自身免疫性脑脊髓炎（EAE）的影响，女士的模型
结果：我们证明，全身和局部给药IL-9可显著改善临床残疾，减少神经炎症，减轻EAE中的突触损伤。结果揭示了IL-9对抗小胶质细胞和TNF介导的神经元兴奋性毒性的未识别的中枢作用。出现了两个主要机制:第一，IL-9通过增强在骨髓细胞-2（TREM2）上表达的触发受体的表达和减少TNF释放来调节小胶质细胞的炎症活性。第二,IL-9抑制神经元TNF信号,从而阻断其突触毒性作用。
结论：这项工作中提供的数据强调了IL-9作为一种关键的神经保护分子，能够干扰EAE中的炎性突触病。这些发现为针对与MS相关的神经退行性损伤的治疗开辟了新的途径。以及中枢神经系统的其他炎症和神经退行性疾病。
