Arenas Yaiza M, López-Gramaje Adrià, Montoliu Carmina, Llansola Marta, Felipo Vicente
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.
Biol Res. 2024 Apr 27;57(1):18. doi: 10.1186/s40659-024-00504-2.
Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia reproduce these alterations. Motor incoordination in hyperammonemic rats is due to increased GABAergic neurotransmission in cerebellum, induced by neuroinflammation, which enhances TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway activation. The initial events by which hyperammonemia triggers activation of this pathway remain unclear. MHE in cirrhotic patients is triggered by a shift in inflammation with increased IL-17. The aims of this work were: (1) assess if hyperammonemia increases IL-17 content and membrane expression of its receptor in cerebellum of hyperammonemic rats; (2) identify the cell types in which IL-17 receptor is expressed and IL-17 increases in hyperammonemia; (3) assess if blocking IL-17 signaling with anti-IL-17 ex-vivo reverses activation of glia and of the TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway.
IL-17 levels and membrane expression of the IL-17 receptor are increased in cerebellum of rats with hyperammonemia and MHE, leading to increased activation of IL-17 receptor in microglia, which triggers activation of STAT3 and NF-kB, increasing IL-17 and TNFα levels, respectively. TNFα released from microglia activates TNFR1 in Purkinje neurons, leading to activation of NF-kB and increased IL-17 and TNFα also in these cells. Enhanced TNFR1 activation also enhances activation of the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway which mediates microglia and astrocytes activation.
All these steps are triggered by enhanced activation of IL-17 receptor in microglia and are prevented by ex-vivo treatment with anti-IL-17. IL-17 and IL-17 receptor in microglia would be therapeutic targets to treat neurological impairment in patients with MHE.
肝硬化患者可能表现出轻微肝性脑病（MHE），伴有轻度认知障碍和运动不协调。慢性高氨血症大鼠会重现这些改变。高氨血症大鼠的运动不协调是由于神经炎症诱导小脑内GABA能神经传递增加，从而增强了TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB途径的激活。高氨血症触发该途径激活的初始事件尚不清楚。肝硬化患者的MHE是由炎症转变和IL-17增加所触发的。本研究的目的是：（1）评估高氨血症是否会增加高氨血症大鼠小脑内IL-17的含量及其受体的膜表达；（2）确定表达IL-17受体且在高氨血症中IL-17增加的细胞类型；（3）评估在体外使用抗IL-17阻断IL-17信号是否能逆转胶质细胞激活以及TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB途径的激活。
高氨血症和MHE大鼠的小脑内IL-17水平和IL-17受体的膜表达增加，导致小胶质细胞中IL-17受体的激活增加，进而分别触发STAT3和NF-kB的激活，使IL-17和TNFα水平升高。小胶质细胞释放的TNFα激活浦肯野神经元中的TNFR1，导致这些细胞中NF-kB的激活以及IL-17和TNFα的增加。TNFR1激活增强还会增强介导小胶质细胞和星形胶质细胞激活的TNFR1-S1PR2-CCL2-BDNF-TrkB途径的激活。
所有这些步骤均由小胶质细胞中IL-17受体的激活增强所触发，并可通过体外抗IL-17治疗来预防。小胶质细胞中的IL-17和IL-17受体可能是治疗MHE患者神经功能障碍的治疗靶点
