New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, Animal Experimental Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, Animal Experimental Center, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Ecotoxicol Environ Saf. 2024 Mar 1;272:116072. doi: 10.1016/j.ecoenv.2024.116072. Epub 2024 Feb 10.
Triptolide (TP) is the major bioactive component of traditional Chinese medicine Tripterygium wilfordii Hook. F., a traditional Chinese medicinal plant categorized within the Tripterygium genus of the Celastraceae family. It is recognized for its therapeutic potential in addressing a multitude of diseases. Nonetheless, TP is known to exhibit multi-organ toxicity, notably hepatotoxicity, which poses a significant concern for the well-being of patients undergoing treatment. The precise mechanisms responsible for TP-induced hepatotoxicity remain unresolved. In our previous investigation, it was determined that TP induces heightened hepatic responsiveness to exogenous lipopolysaccharide (LPS). Additionally, natural killer (NK) cells were identified as a crucial effector responsible for mediating hepatocellular damage in this context. However, associated activating receptors and the underlying mechanisms governing NK cell represented innate lymphoid cell (ILC) activation remained subjects of inquiry and were not yet investigated. Herein, activating receptor Killer cell lectin like receptor K1 (NKG2D) of group 1 ILCs was specifically upregulated in TP- and LPS-induced acute liver failure (ALF), and in vivo blockade of NKG2D significantly reduced group 1 ILC mediated cytotoxicity and mitigated TP- and LPS-induced ALF. NKG2D ligand UL16-binding protein-like transcript 1 (MULT-1) was found upregulated in liver resident macrophages (LRMs) after TP administration, and LRMs did exhibit NK cell activating effect. Furthermore, M1 polarization of LRMs cells was observed, along with an elevation in intracellular tumor necrosis factor (TNF)-α levels. In vivo neutralization of TNF-α significantly alleviated TP- and LPS-induced ALF. In conclusion, the collaborative role of group 1 ILCs and LRMs in mediating hepatotoxicity was confirmed in TP- and LPS-induced ALF. TP-induced MULT-1 expression in LRMs was the crucial mechanism in the activation of group 1 ILCs via MULT-1-NKG2D signal upon LPS stimulation, emphasizing the importance of infection control after TP administration.
雷公藤红素（TP）是传统中药雷公藤（Tripterygium wilfordii Hook. F.）的主要生物活性成分，属于卫矛科雷公藤属植物。它具有治疗多种疾病的潜力。然而，TP 已知具有多器官毒性，特别是肝毒性，这对接受治疗的患者的健康构成了重大威胁。TP 诱导肝毒性的确切机制仍未解决。在我们之前的研究中，已经确定 TP 诱导肝脏对外源脂多糖（LPS）的反应性增加。此外，自然杀伤（NK）细胞被鉴定为介导这一过程中肝细胞损伤的关键效应物。然而，与 NK 细胞相关的激活受体以及调节 NK 细胞代表固有淋巴细胞（ILC）激活的潜在机制仍然是研究的主题，尚未进行研究。在此，我们发现 ILC1 中的激活受体 Killer cell lectin like receptor K1（NKG2D）在 TP 和 LPS 诱导的急性肝衰竭（ALF）中特异性地上调，体内阻断 NKG2D 可显著减少 ILC1 介导的细胞毒性并减轻 TP 和 LPS 诱导的 ALF。在 TP 给药后，肝驻留巨噬细胞（LRMs）中发现 NKG2D 配体 UL16-binding protein-like transcript 1（MULT-1）上调，并且 LRM 确实具有 NK 细胞激活作用。此外，还观察到 LRMs 细胞的 M1 极化，以及细胞内肿瘤坏死因子（TNF）-α水平升高。体内中和 TNF-α可显著减轻 TP 和 LPS 诱导的 ALF。总之，在 TP 和 LPS 诱导的 ALF 中证实了 ILC1 和 LRMs 在介导肝毒性方面的协同作用。TP 在 LRMs 中诱导 MULT-1 的表达是 LPS 刺激后通过 MULT-1-NKG2D 信号激活 ILC1 的关键机制，强调了 TP 给药后感染控制的重要性。
