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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2024

Open Access 01-12-2024 | Research

Deficiency of leucine-rich repeat kinase 2 aggravates thioacetamide-induced acute liver failure and hepatic encephalopathy in mice

Authors: Dan Li, Shu-fang Yu, Lin Lin, Jie-ru Guo, Si-mei Huang, Xi-lin Wu, Han-lin You, Xiao-juan Cheng, Qiu-yang Zhang, Yu-qi Zeng, Xiao-dong Pan

Published in: Journal of Neuroinflammation | Issue 1/2024

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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.
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Metadata
Title
Deficiency of leucine-rich repeat kinase 2 aggravates thioacetamide-induced acute liver failure and hepatic encephalopathy in mice
Authors
Dan Li
Shu-fang Yu
Lin Lin
Jie-ru Guo
Si-mei Huang
Xi-lin Wu
Han-lin You
Xiao-juan Cheng
Qiu-yang Zhang
Yu-qi Zeng
Xiao-dong Pan
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2024
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-024-03125-4

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