Silencing the Tlr4 Gene Alleviates Methamphetamine-Induced Hepatotoxicity by Inhibiting Lipopolysaccharide-Mediated Inflammation in Mice

摘要

Methamphetamine (METH) is a stimulant drug. METH abuse induces hepatotoxicity, although the mechanisms are not well understood. METH-induced hepatotoxicity was regulated by TLR4-mediated inflammation in BALB/c mice in our previous study. To further investigate the underlying mechanisms, the wild-type (C57BL/6) and Tlr4(-/-) mice were treated with METH. Transcriptomics of the mouse liver was performed via RNA-sequencing. Histopathological changes, serum levels of metabolic enzymes and lipopolysaccharide (LPS), and expression of TLR4-mediated proinflammatory cytokines were assessed. Compared to the control, METH treatment induced obvious histopathological changes and significantly increased the levels of metabolic enzymes in wild-type mice. Furthermore, inflammatory pathways were enriched in the liver of METH-treated mice, as demonstrated by expression analysis of RNA-sequencing data. Consistently, the expression of TLR4 pathway members was significantly increased by METH treatment. In addition, increased serum LPS levels in METH-treated mice indicated overproduction of LPS and gut microbiota dysbiosis. However, antibiotic pretreatment or silencing Tlr4 significantly decreased METH-induced hepatic injury, serum LPS levels, and inflammation. In addition, the dampening effects of silencing Tlr4 on inflammatory pathways were verified by the enrichment analysis of RNA-sequencing data in METH-treated Tlr4(-/-) mice compared to METH-treated wild-type mice. Taken together, these findings implied that Tlr4 silencing, comparable to antibiotic pretreatment, effectively alleviated METH-induced hepatotoxicity by inhibiting LPS-TLR4-mediated inflammation in the liver.

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