Department of Systems Medicine, University of Rome Tor Vergata, Rome, 00133, Italy.
Synaptic Immunopathology Lab, IRCCS San Raffaele Roma, Rome, 00166, Italy.
J Neuroinflammation. 2024 May 14;21(1):128. doi: 10.1186/s12974-024-03120-9.
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.
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.
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.
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.
多发性硬化症（MS）是一种中枢神经系统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）作为一种多功能细胞因子，参与 MS 的病理生理学过程。
通过生化、免疫组织化学和电生理实验，我们研究了白细胞介素-9（IL-9）在实验性自身免疫性脑脊髓炎（EAE），即 MS 模型中，对 C57/BL6 雌性小鼠的外周和中枢给药的影响。
我们证明了系统性和局部给予白细胞介素-9（IL-9）均可显著改善临床残疾，减少神经炎症，并减轻 EAE 中的突触损伤。结果揭示了白细胞介素-9（IL-9）对小胶质细胞和 TNF 介导的神经元兴奋性毒性的一种未被认识的中枢作用。出现了两种主要机制：首先，白细胞介素-9（IL-9）通过增强髓样细胞触发受体-2（TREM2）的表达和减少 TNF 的释放，调节小胶质细胞的炎症活性。其次，白细胞介素-9（IL-9）抑制神经元 TNF 信号，从而阻断其突触毒性作用。
本工作中提出的这些数据强调了白细胞介素-9（IL-9）作为一种关键的神经保护分子，能够干扰 EAE 中的炎症性突触病。这些发现为针对 MS 相关神经退行性损伤以及中枢神经系统的其他炎症和神经退行性疾病的治疗开辟了新的途径。
