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Triptolide Induces Liver Injury by Regulating Macrophage Recruitment and Polarization via the Nrf2 Signaling Pathway
1Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
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.
Insights
Triptolide (TP) causes liver injury by inhibiting the Nrf2 pathway, which impairs hepatic macrophages. Activating Nrf2 may protect against TP-induced liver damage by regulating macrophage polarization.
Area of Science:
- Immunology
- Hepatology
- Toxicology
Background:
- Triptolide (TP) causes significant liver injury, limiting its clinical use.
- Hepatic macrophages are crucial in liver immunity and are modulated by TP.
- The protective role of the nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway in TP-induced liver damage is known, but its effect on hepatic macrophages is unclear.
Purpose of the Study:
- To investigate if TP regulates hepatic macrophage recruitment and polarization by inhibiting the Nrf2 signaling pathway.
- To determine the role of Nrf2-mediated hepatic macrophage polarization in TP-induced hepatotoxicity.
Main Methods:
- TP treatment was used to assess its effects on Nrf2 signaling in hepatic macrophages.
- Macrophage recruitment and polarization were analyzed in vivo and in vitro.
- Nrf2 agonists and deficiency models were employed to evaluate their impact on TP-induced liver injury.
Main Results:
- TP was found to inhibit the Nrf2 signaling pathway in hepatic macrophages.
- TP-induced alterations in hepatic macrophages increased susceptibility to inflammatory stimuli, leading to severe liver damage upon subsequent lipopolysaccharide challenge.
- Nrf2 agonists protected macrophages from TP toxicity, while Nrf2 deficiency exacerbated liver injury by promoting macrophage recruitment and M1 polarization.
Conclusions:
- The Nrf2 signaling pathway is a key regulator of hepatic macrophage polarization in the context of TP-induced liver damage.
- Nrf2-mediated hepatic macrophage polarization plays a critical role in the pathogenesis of TP hepatotoxicity.
- Targeting the Nrf2 pathway in hepatic macrophages presents a potential therapeutic strategy for mitigating TP-induced liver injury.
