The hepatoprotective effects of XCHD and MgIG against methotrexate-induced liver injury and inflammation in rats through suppressing the activation of AIM2 inflammasomes.

Background: Recent studies have shown that drug-induced liver injury may be related to the immune response activated by drugs. A cytosolic dsDNA inflammasome called absent in melanoma 2 (AIM2) was found to be associated with aseptic inflammation. The present study aimed to explore the effects of on the liver injury and inflammation in methotrexate (Mtx)-induced rats.

Methods: Sprague Dawley (SD) rats were selected and classified into 4 groups randomly, includes control group, Mtx group, Mtx-Xiaochaihu decoction (XCHD) group and Mtx-magnesium isoglycyrrhizinate (MgIG) group. Light microscopy was used to examine histological specimens after hematoxylin-eosin (HE) staining. The AST levels in liver tissue and blood serum ALT in the rats were assessed with enzyme linked immunosorbent assay (ELISA). Then AIM2 expression and inflammatory factors, including caspase-1, IL-18, and IL-1β, in the liver biopsy specimens of rats were detected by immunohistochemistry. Furthermore, the correlation between inflammatory and AIM2 expression factors was comprehensively analyzed.

Results: Functional and structural hepatotoxicity can be caused by the exposure to Mtx, which was supported by the improved biochemical marker levels and the worse histopathological changes in liver tissue. Compared with the Mtx group, the levels of liver enzymes ALT and AST, histological deterioration in the liver tissues were effectively decreased by XCHD and MgIG treatment, respectively. In addition, the expression of AIM2, caspase-1 and IL-1β was observably higher in the Mtx group, which was apparently inhibited in the Mtx-XCHD and Mtx-MgIG groups. There was no obvious change in IL-18 expression among four groups. AIM2 expression were positively associated with the severity of liver inflammation and had a higher relevance with caspase-1 expression.

Conclusions: AIM2 inflammasome in hepatocytes has a significant effect on the development of Mtx-induced liver injury, which can be ameliorated by both XCHD and MgIG treatment. The latent mechanism and potential signal pathway require further study.