Role of macrophage AHR/TLR4/STAT3 signaling axis in the colitis induced by non-canonical AHR ligand aflatoxin B1.
J Hazard Mater
; 452: 131262, 2023 06 15.
Article
em En
| MEDLINE
| ID: mdl-36989784
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aflatoxina B1
/
Colite
Tipo de estudo:
Observational_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Hazard Mater
Assunto da revista:
SAUDE AMBIENTAL
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China