Macrophage MAPK7/AhR/STAT3 Signaling Mediates Mitochondrial ROS Burst and Enterohepatic Inflammatory Responses Induced by Deoxynivalenol Relevant to Low-Dose Exposure in Children

Abstract

Deoxynivalenol (DON) can induce endoplasmic reticulum (ER) stress, mitochondrial ROS burst, and macrophage polarization. Here, we investigated the mechanism linking the above three aspects with the dose range relevant to low-level exposure in children. At 0.5 μg/kg bw/day, we found remarkable liver and gut inflammatory responses after 6-week exposure in mice age comparable to humans 7-12 years old. Through antioxidant intervention, we found that ROS played a driver role in macrophage polarization and inflammatory responses induced by DON in the liver and gut. Further bioinformatics analysis uncovered that ER stress-associated protein MAPK7 (ERK5) may bind with AhR to initiate a mitochondrial ROS burst and macrophage M1 polarization. The downstream cellular events of MAPK7-AhR interaction may be mediated by the AhR/STAT3/p-STAT(Ser727) pathway. This mechanism was further supported by DON toxicity mitigation using cyanidin-3-glucoside (C-3-G), which docks to MAPK7 oligomerization region 200-400 aa and disrupts MAPK7-AhR interaction. Overall, our study provides novel evidence and mechanism for DON-induced inflammatory responses in the liver and gut system. Our findings call attention to the health risks associated with low-level DON exposure in the prepuberty children population.

Keywords: aryl hydrocarbon receptor; deoxynivalenol; macrophage; mitochondrial ROS; mitogen-activated protein kinase 7.