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

Abstract

Trichloroethylene (TCE)induces occupational medicamentosa-like dermatitis due to TCE (OMDT)with immune liver injury, and TNF-αplays an important role in macrophage polarization and liver injury. However, TNF-αregulating 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-mTORprotein increased induce by TCE. In vitro, we found TNFR1 and CD11c were increased in RAW264.7cell line with TNF-α.And then we use Zafirlukast (Zaf), an TNFR1 antagonist, CD11c and TNFR1 reduced significantly, we also found p-mTORexpression increased after TNF-αtreatment, but decreased in TNF-α+ 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-mTORproteins increased and LC3B decreased in the TCE positive group, while RAP treatment reversed the trends of all of these proteins. Rapamycin prevented the TNF-α-induced p-mTOR increase and dramatically downregulated IL-1β expression in the RAW264.7cell line with TNF-αtreatment. The results uncover a novel role for TNF-α/TNFR1,which promotes M1 polarization of macrophage and suppresses macrophage autophagy via the mTOR pathway.