Induction of TRIM22 during Clonorchis sinensis infection triggers intracellular ROS accumulation by suppressing the mTOR-mediated Nrf2 signaling pathway.

BACKGROUND

Clonorchis sinensis infection triggers various hepatobiliary complications, including epithelial hyperplasia, chronic inflammation, periductal fibrosis, and cholangiocarcinogenesis through direct contact with worms and their excretory-secretory products (ESPs). We previously profiled differential transcriptome expression from three-dimensional cholangiocyte (H69 cells) spheroids constitutively and repetitively exposed to ESPs using microarrays and RNA-seq analysis. TRIM22 was upregulated in response to ESP exposure.

OBJECTIVE

This study aimed to elucidate the pathophysiological mechanism of TRIM22-mediated hepatobiliary abnormalities during C. sinensis infection.

METHODS

Quantitative reverse transcription polymerase chain reaction and immunoblot analyses were used to examine TRIM22 transcript and protein expression in ESP-treated H69 spheroids and 2D cultured cells. Transfection with TRIM22-specific small interfering RNA was performed to examine changes in intracellular reactive oxygen species levels and the expression of the redox-active transcription factor signaling pathway (mTOR/Nrf2) and its target genes. Liver tissues from C. sinensis-infected mice were stained with TRIM22 and Nrf2 polyclonal antibodies.

RESULTS

Treatment of H69 cells with ESPs increased TRIM22 expression and AKT/mTOR signaling pathway activation. TRIM22 knockdown abolished ESP-induced mTOR activation but elevated Nrf2 nuclear translocation with subsequent increased expression of antioxidant and phase II detoxifying enzymes. The immunoreactivity of TRIM22 and Nrf2 showed distinctly different patterns in the liver of mouse infected with C. sinensis for three months.

CONCLUSION

TRIM22 upregulation during C. sinensis infection contributes to hepatobiliary abnormalities by disrupting redox homeostasis.