PUMA upregulation promotes the necroptosis of hepatocytes in trichloroethylene-sensitized mice via mtDNA-mediated ZBP1 pathway.

Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) caused by trichloroethylene (TCE) is a systemic allergic disease mainly manifested by acute inflammatory reactions in the skin and mucosa. In addition to fever, skin and mucosal damage, superficial lymph node enlargement and tenderness, OMDT patients often have severe multi-organ damage, with liver function damage being the most common. The degree of liver function injury can seriously affect the cure rate of OMDT, but the mechanism of injury has not been fully elucidated. The aim of our study was to explore the mechanism of mitochondrial DNA (mtDNA) release and the role of mtDNA in trichloroethylene-sensitized liver injury. Previous studies found amounts of tumor necrosis factor TNF- α in the liver of mice sensitized to TCE. Moreover, we found a leakage of mtDNA during TCE sensitization. Mitochondrial DNA Exposure to cytosol can activate innate immune responses and play a key role in immune liver injury induced by TCE, but the mechanism by which mtDNA is released to the cellular cytoplasm is unknown. In this study, we found that TNF-α promotes the upregulation of PUMA (p53 upregulated modulator of apoptosis) pro-apoptotic proteins in the liver of TCE-sensitized mice, and then PUMA promotes mtDNA release by regulating the mitochondrial BAX / BAK apoptotic pore, and subsequently activates the DNA sensor ZBP1 (Z-DNA Binding Protein 1), which ultimately leads to RIPK3 / MLKL-dependent necroptosis in hepatocytes.