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Macrophage MAPK7/AhR/STAT3 Signaling Mediates Mitochondrial ROS Burst and Enterohepatic Inflammatory Responses
Qi Zhang1, Ming Liu2, Jing Zhang3
1Department of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan,Shandong 250012, China.
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.
Insights
Low-level deoxynivalenol (DON) exposure causes liver and gut inflammation in children via endoplasmic reticulum stress and reactive oxygen species (ROS). Antioxidants and cyanidin-3-glucoside (C-3-G) mitigate DON
Area of Science:
- Toxicology
- Immunology
- Molecular Biology
Background:
- Deoxynivalenol (DON) is a common food contaminant.
- DON exposure is linked to endoplasmic reticulum (ER) stress, mitochondrial reactive oxygen species (ROS) burst, and macrophage polarization.
- Low-level DON exposure risks in children require mechanistic understanding.
Purpose of the Study:
- Investigate the mechanism linking ER stress, ROS, and macrophage polarization in low-level DON exposure.
- Determine the role of ROS in DON-induced inflammation.
- Identify molecular targets for mitigating DON toxicity.
Main Methods:
- 6-week exposure of mice (comparable to 7-12 year old children) to 0.5 μg/kg bw/day DON.
- Antioxidant intervention to assess ROS role.
- Bioinformatics analysis to identify protein interactions (MAPK7, AhR).
- Cyanidin-3-glucoside (C-3-G) intervention to test mitigation strategy.
Main Results:
- Low-level DON exposure induced significant liver and gut inflammation.
- ROS confirmed as a driver of macrophage polarization and inflammation.
- MAPK7-AhR interaction identified as a key pathway initiating ROS burst and M1 macrophage polarization.
- C-3-G disrupted MAPK7-AhR interaction, mitigating DON toxicity.
Conclusions:
- A novel mechanism for DON-induced liver and gut inflammation involving ER stress, MAPK7-AhR interaction, ROS burst, and M1 macrophage polarization is elucidated.
- ROS plays a critical role in mediating DON's inflammatory effects.
- Findings highlight potential health risks of low-level DON exposure in prepubescent children and suggest C-3-G as a potential countermeasure.
