2. Academic Validation
  3. Role of macrophage AHR/TLR4/STAT3 signaling axis in the colitis induced by non-canonical AHR ligand aflatoxin B1

Role of macrophage AHR/TLR4/STAT3 signaling axis in the colitis induced by non-canonical AHR ligand aflatoxin B1

  • J Hazard Mater. 2023 Mar 23;452:131262. doi: 10.1016/j.jhazmat.2023.131262.
Liwen Zhang 1,  Dong Cheng 2,  Jing Zhang 2,  Hui Tang 2,  Fenghua Li 2,  Yi Peng 3,  Xinglan Duan 3,  En Meng 3,  Cuili Zhang 1,  Tao Zeng 1,  Fuyong Song 1,  Jia-Sheng Wang 4,  Xiulan Zhao 5,  Jun Zhou 6
Affiliations

Affiliations

  • 1 Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 250012, China; Division of Chemistry and Physics, Shandong Center for Disease Control and Prevention, Jinan 250014, China.
  • 2 Division of Toxicology, Shandong Center for Disease Control and Prevention, Jinan 250014, China; Division of Chemistry and Physics, Shandong Center for Disease Control and Prevention, Jinan 250014, China.
  • 3 Division of Chemistry and Physics, Shandong Center for Disease Control and Prevention, Jinan 250014, China; School of Public Health, Cheeloo College of Medicine, Shandong University, 250012, China.
  • 4 Division of Chemistry and Physics, Shandong Center for Disease Control and Prevention, Jinan 250014, China; Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, GA 30602, USA.
  • 5 Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 250012, China; Division of Chemistry and Physics, Shandong Center for Disease Control and Prevention, Jinan 250014, China. Electronic address: zhao.xl@sdu.edu.cn.
  • 6 Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 250012, China; Division of Chemistry and Physics, Shandong Center for Disease Control and Prevention, Jinan 250014, China. Electronic address: zhjccm@sdu.edu.cn.
PMID: 36989784 DOI: 10.1016/j.jhazmat.2023.131262
Abstract

Here we report that macrophage AHR/TLR/STAT signaling axis is implicated in the colon colitis induced by non-canonical AHR ligand aflatoxin B1 (AFB1). In BALB/c mice gavaged with 5, 25 and 50 µg/kg body weight/day AFB1, we observed severe colitis featured by over-recruitment of myeloid lineage immune cells such as monocytes/macrophage in colon lamina propria. Stressed and damaged colon epithelial cells were observed in low-dose group, while twisted and shortened intestinal crypts being found in middle dose group. Severe tissue damage was induced in the high-dose group. Dose-dependent increases of ROS, NO, and decrease of mitochondrial ROS-suppressor STAT3 were observed in the exposure groups. Further investigation in AFB1-treated human macrophage model found: (1) functional adaptations such as elevation of TNF-alpha and IL-6 secretion, stimulation of phagocytosis, elevation of LTE4 level; (2) overall inflammatory status confirmed by RNA-sequence analysis, in line with up-regulation of immune functional proteins such as ICAM-1, IDO-1, NF-kB-p65, NLRP3, COX-2 and iNOS; (3) mRNA disruption of mitochondrial Oxidative Phosphorylation complex I units and STATs; (4) perturbation of AHR/TLR/STAT3 signaling axis, including elevated AHR, TLR2, TLR4, and decreased STAT3, p-STAT3 Ser727. Mechanism investigation revealed regulatory links of ligand-dependent AHR/TLR4/STAT3. AHR-TLR4 together regulate MyD88, and STAT3 may be directly regulated by MyD88 (TLR4 downstream molecule) upon AHR/TLR4 binding with ligands. Solely protein level changes of AHR/TLR4 cannot regulate STAT3. Our study suggests that macrophage AHR/TLR4/STAT3 is involved with the colitis induced by sub-acute exposure to AFB1. Future follow-up study will focus on the intervention of the colitis using AHR-anti-inflammatory ligands.

Keywords

Aflatoxin B1; Aryl hydrocarbon receptor; Colitis; Macrophage; Mitochondrial ROS.

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