Triptolide Induces Liver Injury by Regulating Macrophage Recruitment and Polarization via the Nrf2 Signaling Pathway

Abstract

Triptolide (TP) has limited usage in clinical practice due to its side effects and toxicity, especially liver injury. Hepatic macrophages, key player of liver innate immunity, were found to be recruited and activated by TP in our previous study. The nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway exerts a protective role in TP-induced liver damage, but its effect on the functions of hepatic macrophage has not been elucidated. Here, we determined whether TP can regulate the recruitment and polarization of hepatic macrophages by inhibiting Nrf2 signaling cascade. Our results demonstrated that TP inhibited the Nrf2 signaling pathway in hepatic macrophages. The changes in hepatic macrophages were responsible for the increased susceptibility toward inflammatory stimuli, and hence, TP pretreatment could induce severe liver damage upon the stimulation of a nontoxic dose of lipopolysaccharides. In addition, the Nrf2 agonist protected macrophages from TP-induced toxicity and Nrf2 deficiency significantly aggravated liver injury by enhancing the recruitment and M1 polarization of hepatic macrophages. This study suggests that Nrf2 pathway-mediated hepatic macrophage polarization plays an essential role in TP-induced liver damage, which can serve as a potential therapeutic target for preventing hepatotoxicity induced by TP.

The molecular pathogenesis of triptolide-induced hepatotoxicity

“…Hepatic macrophages are the most abundant hepatic immune cells which play a vital role in maintaining hepatic homeostasis and contribute to the progression of DILI ( Tsuji et al, 2020 ). Several studies have shown that TP inhibited the phagocytosis of macrophages, increased the number of macrophages, and modulated the polarization of macrophages in mice ( Wang L. et al, 2018 ; Liu L. et al, 2022 ). what’s more, in a study of TP-induced acute hepatotoxicity, researchers found that depletion of macrophages using clodronate liposomes pretreatment could suppress the inflammatory response and alleviated TP-induced hepatotoxicity ( Zhao, 2018 ).…”

“…Researchers further found that the imbalance of hepatic immune homeostasis was caused by TP-induced inhibition of NF-κB-dependent transcriptional activity and CASP8 and FADD like apoptosis regulator (CFLAR, also known as FLIP) production ( Yuan et al, 2020 ). Furthermore, TP inhibited the phagocytic function of macrophages, increased the number of macrophages, and regulated macrophages polarization in the mouse liver, resulting in an amplification of the inflammatory response to a non-hepatotoxic dose of LPS and exacerbated hepatotoxicity ( Wang L. et al, 2018 ; Liu L. et al, 2022 ). Recently, it was found that the immune disorder caused by a TP-induced Th17/Treg imbalance was also the cause of liver intolerance to a non-hepatotoxic dose of LPS in TP-induced acute hepatotoxicity ( Zhang H. et al, 2022 ).…”