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Published on: July 26, 2017
M1 macrophage activation via TLR4/NF-κB/mincle is essential for triptolide-induced hepatotoxicity
Ruoting Ding1, Qingfeng Miao2, Xindi Ma3
1Department of Pharmacology, The Key Laboratory of Pharmacology and Toxicology for New Drugs, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, PR China; Department of Pharmacy, The Third Hospital of Shijiazhuang, Hebei, PR China.
Ethnopharmacology Relevance:
Triptolide (TP), extracted from the traditional Chinese herb Tripterygium wilfordii (T. wilfordii) Hook f., is a major bioactive ingredient with potent antitumor, immunosuppressive biological activities. However, its narrow therapeutic window and high toxicity greatly limit its clinical use. Therefore, uncovering the molecular mechanisms responsible for hepatotoxicity is critical for safe clinical application.
Aim Of The Study:
This research was designed to investigate the role of macrophage M1 polarization in TP-induced hepatotoxicity and to explore the mechanisms.
Materials And Method:
Mincle expression was examined in TP-induced mouse model of liver injury, the activation of TLR4/NF-κB/Mincle pathway and macrophage polarization were examined using Western Blot, q-PCR, ELISA, immunohistochemistry and molecular docking in a mouse model of knockout Mincle and a model of macrophage inflammation. In addition, AML12 cells were stimulated with RAW264.7 cell supernatant after TP stimulation to observe the changes of the cell numbers and damage.
Results:
Numerous inflammatory factors released from M1 polarization of macrophages in TP-induced liver injury, the activation of TLR4/NF-κB/Mincle pathway played a key role in M1 polarization of macrophages. Knockout of Mincle in overall experiments reversed TP-induced liver injury. The results of in vitro experiments showed that substances released from TP-stimulated polarization of RAW264.7 cells had a killing effect on hepatic parenchymal cells, as evidenced by increased SAP130 release and cellular autophagy impairment, and that inhibitors of TLR4 effectively reduced Mincle expression and cellular M1 polarization in RAW264.7 cells.
Conclusions:
These results demonstrate that M1 macrophage activation, mediated by the TLR4/NF-κB/Mincle pathway, is essential for TP-induced hepatotoxicity, and Mincle was a promising therapeutic target for mitigating TP's hepatotoxicity.
