Macrophage AHR-TLR4 cross-talk drives p-STAT3 (Ser727)-mediated mitochondrial oxidative stress and upregulates IDO/ICAM-1 in the steatohepatitis induced by aflatoxin B1

• Published in: The Science of the total environment 2024-05, Vol.923, p.171377-171377, Article 171377
• Main Authors: Zhang, Jing, Liu, Hui, Shen, Yang, Cheng, Dong, Tang, Hui, Zhang, Qi, Li, Chao, Liu, Ming, Yao, Wenhuan, Ran, Rongrong, Hou, Qingzhen, Zhao, Xiulan, Wang, Jia-Sheng, Sun, Xiulan, Zhang, Tianliang, Zhou, Jun
• Format: Article
• Language: English
• Subjects: Aflatoxin B1; Aryl hydrocarbon receptor; Macrophage polarization; Mitochondrial ROS; Steatohepatitis
• ISSN: 0048-9697; 1879-1026
• DOI: 10.1016/j.scitotenv.2024.171377

Aflatoxin B1 (AFB1) is a major mycotoxin contaminant showing in the environment and foods. In this study, the molecular initiating events (MIEs) of AFB1-induced steatohepatitis were explored in mice and human cell model. We observed dose-dependent steatohepatitis in the AFB1-treated mice, including triglyceride accumulation, fibrotic collagen secretion, enrichment of CD11b + and F4/80+ macrophages/Kupffer cells, cell death, lymphocytes clusters and remarkable atrophy areas. The gut barrier and gut-microbiota were also severely damaged after the AFB1 treatment and pre-conditioned colitis in the experimental mice aggravated the steatohepatitis phenotypes. We found that macrophages cells can be pro-inflammatorily activated to M1-like phenotype by AFB1 through an AHR/TLR4/p-STAT3 (Ser727)-mediated mitochondrial oxidative stress. The phenotypes can be rescued by AHR inhibitors in the mice model and human cell model. We further showed that this signaling axis is based on the cross-talk interaction between AHR and TLR4. Gene knock-up experiment found that the signaling is dependent on AFB1 ligand-binding with AHR, but not protein expressions of TLR4. The signaling elevated NLRP3 and two immune metabolic enzymes ICAM-1 and IDO that are associated with macrophage polarization. Results from intervention experiments with natural anti-oxidant and AHR inhibitor CH223191 suggest that the macrophage polarization may rely on AHR and ROS. Our study provides novel and critical references to the food safety and public health regulation of AFB1. [Display omitted] •The molecular mechanism of AFB1-induced steatohepatitis was investigated.•The steatohepatitis is driven by AHR-TLR4 crosstalk and p-STAT3/ROS axis.•ROS demonstrates a mediator role between upstream MIEs and downstream toxicities.•AFB1 induced elevation of immune metabolic enzymes ICAM-1 and IDO in macrophages.•A toxicity mechanism based on “AHR-TLR4 crosstalk/p-STAT3” is proposed.