Ameliorative role of AhR ligands in concanavalin-induced liver injury is due to increased miR-100 expression leading to mTOR downregulation and promoter hydroxymethylation

Autor: Alkeiver S Cannon, Prakash Nagarkatti, Mitzi Nagarkatti
Rok vydání: 2022
Předmět:
Zdroj: The Journal of Immunology. 208:60.06-60.06
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.208.supp.60.06
Popis: The promiscuous aryl hydrocarbon receptor (AhR) has long been the target of immunological studies due to its expression on many immune cells. However, the specific mechanisms underlying the role of AhR activation in inflammatory disease has not been elucidated. We employed a murine model of immune cell-mediated liver injury, comparable to autoimmune hepatitis (AIH) in humans, by intravenously injecting 12.5 mg/kg of Concanavalin A (ConA) and treating one hour later via intraperitoneal injection with an AhR ligand: 10 μg/kg 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) or 50 μg/kg 6-formylindolo[3,2-b] carbazole (FICZ). Our studies showed that both ligands improved the clinical parameters of AIH in this model. 24 hours after challenge, liver mononuclear cells were harvested, and total RNA and DNA were isolated. We examined the underlying mechanisms by conducting small RNA-sequencing and discovered dysregulation of many miRNAs. Of note, miR-100 was significantly upregulated, and we found this molecule to contain a dioxin-responsive element (DRE) in its promoter region. Further, we conducted methylated and hydroxymethylated DNA immunoprecipitation sequencing on CD45+ cells in this model and found distinct methylation profiles between each of the groups. Specifically, we observed increased hydroxymethylation in both treatment groups as compared to the ConA+Vehicle group in the promoter of mTOR, a direct target of miR-100. These data suggest that AhR activation reduces liver injury by upregulating miR-100 and reducing mTOR activity. Additionally, hydroxymethylation of the mTOR promoter may contribute to the changes observed upon AhR activation, thus lending credence for a role of hydroxymethylation in cell differentiation. Supported by NIH grants P01AT003961, P20GM103641, R01ES030144, R01AI129788 and R01AI123947, R01AI160896 and R01AI123947-04S1
Databáze: OpenAIRE
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