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Abstract：
BACKGROUND: Hepatic encephalopathy (HE) is closely associated with inflammatory responses. However, as a crucial regulator of the immune and inflammatory responses, the role of leucine-rich repeat kinase 2 (LRRK2) in the pathogenesis of HE remains unraveled. Herein, we investigated this issue in thioacetamide (TAA)-induced HE following acute liver failure (ALF).
METHODS: TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2G2019S) and LRRK2 knockout (Lrrk2-/-) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed.
RESULTS: The Lrrk2-/--HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p < 0.05), with no difference found between the WT-HE and Lrrk2G2019S-HE groups. Compared with the other groups, after the TAA injection, the Lrrk2-/- group displayed a significant increase in ammonium and pro-inflammatory cytokines, aggravated hepatic inflammation/necrosis, decreased autophagy, and abnormal phosphorylation of lysosomal Rab10. All three models reported microglial activation, neuronal loss, disordered vesicle transmission, and damaged myelin structure. The Lrrk2-/--HE mice presented no severer neuronal injury than the other genotypes.
CONCLUSIONS: LRRK2 deficiency may exacerbate TAA-induced ALF and HE in mice, in which inflammatory response is evident in the brain and aggravated in the liver. These novel findings indicate a need of sufficient clinical awareness of the adverse effects of LRRK2 inhibitors on the liver.
METHODS: TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2G2019S) and LRRK2 knockout (Lrrk2-/-) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed.
RESULTS: The Lrrk2-/--HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p < 0.05), with no difference found between the WT-HE and Lrrk2G2019S-HE groups. Compared with the other groups, after the TAA injection, the Lrrk2-/- group displayed a significant increase in ammonium and pro-inflammatory cytokines, aggravated hepatic inflammation/necrosis, decreased autophagy, and abnormal phosphorylation of lysosomal Rab10. All three models reported microglial activation, neuronal loss, disordered vesicle transmission, and damaged myelin structure. The Lrrk2-/--HE mice presented no severer neuronal injury than the other genotypes.
CONCLUSIONS: LRRK2 deficiency may exacerbate TAA-induced ALF and HE in mice, in which inflammatory response is evident in the brain and aggravated in the liver. These novel findings indicate a need of sufficient clinical awareness of the adverse effects of LRRK2 inhibitors on the liver.
摘要：
背景：肝性脑病（HE）与炎症反应密切相关。然而,作为免疫和炎症反应的关键调节剂，富含亮氨酸的重复激酶2（LRRK2）在HE发病机制中的作用仍未得到阐明。在这里，我们在硫代乙酰胺（TAA）诱导的急性肝衰竭（ALF）后HE中研究了这个问题。
方法：TAA诱导的LRRK2野生型（WT）HE小鼠模型，建立LRRK2G2019S突变(Lrrk2G2019S)和LRRK2敲除(Lrrk2-/-)。进行了一系列神经行为实验。检测生化指标和促炎细胞因子。前额叶皮质(PFC),纹状体(STR),海马(HIP),病理和电镜检查肝脏。分析了自噬-溶酶体途径和关键RabGTP酶活性的变化。
结果：Lrrk2-/--HE模型报告的生存率明显低于其他两种模型（24％vs.48%,分别,p<0.05)，WT-HE和Lrrk2G2019S-HE组之间无差异。与其他组相比，注射TAA后,Lrrk2-/-组显示铵和促炎细胞因子的显着增加，肝脏炎症/坏死加重，自噬减少，溶酶体Rab10的异常磷酸化。所有三个模型都报告了小胶质细胞激活，神经元丢失，无序的囊泡传播，髓鞘结构受损.Lrrk2-/-HE小鼠未表现出比其他基因型更严重的神经元损伤。
结论：LRRK2缺乏可能加剧TAA诱导的小鼠ALF和HE，其中炎症反应在大脑中明显，在肝脏中加重。这些新发现表明需要对LRRK2抑制剂对肝脏的不利影响有足够的临床认识。
方法：TAA诱导的LRRK2野生型（WT）HE小鼠模型，建立LRRK2G2019S突变(Lrrk2G2019S)和LRRK2敲除(Lrrk2-/-)。进行了一系列神经行为实验。检测生化指标和促炎细胞因子。前额叶皮质(PFC),纹状体(STR),海马(HIP),病理和电镜检查肝脏。分析了自噬-溶酶体途径和关键RabGTP酶活性的变化。
结果：Lrrk2-/--HE模型报告的生存率明显低于其他两种模型（24％vs.48%,分别,p<0.05)，WT-HE和Lrrk2G2019S-HE组之间无差异。与其他组相比，注射TAA后,Lrrk2-/-组显示铵和促炎细胞因子的显着增加，肝脏炎症/坏死加重，自噬减少，溶酶体Rab10的异常磷酸化。所有三个模型都报告了小胶质细胞激活，神经元丢失，无序的囊泡传播，髓鞘结构受损.Lrrk2-/-HE小鼠未表现出比其他基因型更严重的神经元损伤。
结论：LRRK2缺乏可能加剧TAA诱导的小鼠ALF和HE，其中炎症反应在大脑中明显，在肝脏中加重。这些新发现表明需要对LRRK2抑制剂对肝脏的不利影响有足够的临床认识。
