Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012, Valencia, Spain.
Departamento de Patología, Facultad de Medicina, Universidad Valencia, Valencia, Spain.
J Neuroinflammation. 2024 Nov 30;21(1):314. doi: 10.1186/s12974-024-03310-5.
Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with motor incoordination which is reproduced in hyperammonemic rats. Hyperammonemia induces peripheral inflammation which triggers neuroinflammation and enhanced GABAergic neurotransmission in cerebellum and motor incoordination. The mechanisms involved remain unknown. The aims were to assess if the early increase of peripheral IL-17 triggers motor incoordination in hyperammonemic rats and to identify some underlying mechanisms. We assessed if blocking peripheral IL-17 with anti-IL-17 at 2-4 days of hyperammonemia prevents motor incoordination and analyzed underlying mechanisms. Hyperammonemia induces a transient blood IL-17 increase at days 3-4. This is associated with increased IL-17 receptor membrane expression and activation in cerebellum, leading to NADPH oxidase activation, increased superoxide production and MLCK that induce blood-brain barrier (BBB) permeabilization by reducing occludin and ZO-1. BBB permeabilization facilitates the entry of IL-17, which increases in cerebellum and activates microglia. This increases TNFα and the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway. This enhances GABAergic neurotransmission which impairs motor coordination. Blocking peripheral IL-17 with anti-IL-17 prevents all the above process and prevents motor incoordination. Early treatment to reduce blood IL-17 may be a useful treatment to reverse motor incoordination in patients with MHE.
肝硬化患者可能会出现轻微的肝性脑病（MHE），伴有运动不协调，这种现象在高氨血症大鼠中重现。高氨血症会引发外周炎症，从而触发小脑和运动不协调的神经炎症和增强 GABA 能神经传递。其涉及的机制尚不清楚。目的是评估外周白细胞介素-17（IL-17）的早期增加是否会引发高氨血症大鼠的运动不协调，并确定一些潜在的机制。我们评估了在高氨血症的第 2-4 天用抗白细胞介素-17（anti-IL-17）阻断外周白细胞介素-17 是否可以预防运动不协调，并分析了潜在的机制。高氨血症在第 3-4 天诱导短暂的血液白细胞介素-17 增加。这与小脑中 IL-17 受体膜表达和激活的增加有关，导致 NADPH 氧化酶激活、超氧化物产生增加和 MLCK 增加，通过减少闭合蛋白和 ZO-1 导致血脑屏障（BBB）通透性增加。BBB 通透性增加有利于白细胞介素-17 的进入，从而增加小脑并激活小胶质细胞。这会增加 TNFα 和 TNFR1-S1PR2-CCL2-BDNF-TrkB 通路。这增强了 GABA 能神经传递，从而损害运动协调。用抗白细胞介素-17 阻断外周白细胞介素-17 可以防止所有上述过程，并防止运动不协调。早期降低血液白细胞介素-17 的治疗可能是逆转 MHE 患者运动不协调的有效治疗方法。
