CpG-oligodeoxynucleotides challenged macrophages ameliorate acetaminophen induced liver injury by activating TLR9/IRG1/itaconate metabolic pathway

作者：Yibai Qu, Zehui Jiang, Zhixia Chen, Si-Dan Luo, Bingyao Xie, Xubo Wu, Gang Yuan, Kai Wu, Li Chen, Tian Tian, Shan Li, Haihua Luo, Quan Li, Yuan Ding, Y. Zhang, Yanxia Gao, Jun Zhou, Zhengzheng Yan, Yong Jiang · 发表于：Molecular Medicine · 年份：2025 · DOI：10.1186/s10020-025-01324-0 · 被引用次数：3 · 研究领域：Drug-Induced Hepatotoxicity and Protection、Immune cells in cancer、Liver physiology and pathology

BACKGROUND: Acetaminophen, or N-acetyl-para-aminophenol (APAP), causes severe liver damage and acute liver failure when overdosed. Oligodeoxynucleotides containing CpG motifs (CpG ODN) can regulate the function of macrophages, which play an important role in drug-induced liver injury. It is unclear whether CpG ODN-treated macrophages play an immune regulation role in APAP-induced liver injury. In the present study, we aim to explore the role of CpG ODN-activated macrophages in APAP-induced liver injury and the underlying mechanism in protecting against the cytotoxicity of APAP. METHODS: In vivo, C57BL/6 mice were treated with APAP (300 mg/Kg) or/and CpG ODN (ODN 1826, 1.65 mg/Kg) by intraperitoneal injection, then survival rate, histopathological evaluation, and inflammatory factors were observed to ascertain the protective effect of CpG ODN. Then, CpG ODN-treated macrophages were reinfused into the animal model to determine the effector cells. In vitro, RNA sequencing and untargeted metabolomics detection were performed to illustrate the underlying mechanism. Last, Acod1 siRNA interference was used to clarify the role of IRG1 in resistance to APAP cytotoxicity by ROS and apoptosis indicator detections. RESULTS: We found that CpG ODN showed a protective effect against APAP cytotoxicity by stimulating macrophages rather than hepatic parenchymal cells. In particular, reinfusion of CpG ODN-treated macrophages to mice can alleviate APAP-induced liver injury. Transcriptome and met...