Macrophage autophagy contributes to immune liver injury in trichloroethylene sensitized mice: Critical role of TNF-α mediating mTOR pathway

Trichloroethylene (TCE) induces occupational medicamentosa-like dermatitis due to TCE (OMDT) with immune liver injury, and TNF-& alpha; plays an important role in macrophage polarization and liver injury. However, TNF-& alpha; regulating macrophage polarization in liver injury induced by TCE is still unknown. Thus, on the basis of our previous research, we established the TCE-sensitized BALB/c mouse model with R7050, a specific inhibitor of TNFR1. Then, we observed significant decreases in autophagy related protein and gene levels in M1 macrophage in TCE positive group, and R7050 can relieve M1 macrophage autophagy. We also found the phosphorylated form of mammalian target of Rapamycin (mTOR) was activated and the expression of p-mTOR protein increased induce by TCE. In vitro, we found TNFR1 and CD11c were increased in RAW264.7 cell line with TNF-& alpha;. And then we use Zafirlukast (Zaf), an TNFR1 antagonist, CD11c and TNFR1 reduced significantly, we also found p-mTOR expression increased after TNF-& alpha; treatment, but decreased in TNF-& alpha; + Zaf group. Further, we used Rapamycin (RAP), a mTOR-specific inhibitor, to establish a TCE-sensitized mice model and found the expression levels of p62 and p-mTOR proteins increased and LC3B decreased in the TCE positive group, while RAP treatment reversed the trends of all of these proteins. Rapamycin prevented the TNF-& alpha;-induced p-mTOR increase and dramatically downregulated IL-1 & beta; expression in the RAW264.7 cell line with TNF-& alpha; treatment. The results uncover a novel role for TNF-& alpha;/TNFR1, which promotes M1 polarization of macrophage and suppresses macrophage autophagy via the mTOR pathway.

Automated summary

Trichloroethylene (TCE) induces occupational medicamentosa-like dermatitis due to TCE (OMDT) with immune liver injury, and TNF-α plays an important role in macrophage polarization and liver injury. This study aimed to investigate the regulatory effects of TNF-α on macrophage polarization and autophagy in TCE-induced liver injury. The results showed that TNF-α/TNFR1 promoted M1 polarization of macrophages and suppressed macrophage autophagy via the mTOR pathway.