Aryl hydrocarbon receptor activation ameliorates experimental colitis by modulating the tolerogenic dendritic and regulatory T cell formation

Background Intestinal immune dysfunction is involved in the onset of Crohn's disease (CD). The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor widely expressed in various immune cells, including DCs. Although AhR plays an important role in immune tolerance, its role in the DCs is unclear. The purpose of this study was to investigate whether the activation of AhR can induce tolerogenic DCs (tolDCs) and the differentiation of regulatory T (Treg) cells, as well as ameliorate experimental colitis. Methods Bone marrow derived DCs were incubated with or without FICZ(100 nM) which was a kind of AhR for 12 hours, subsequently the cells were stimulated to mature. Scanning electron microscope (SEM) was used to observe dendritic formation on DC surface. Proliferation of T lymphocytes was evaluated by proliferation experiment. The expression of surface markers in DCs were detected by flow cytometry and the gene expression levels of cytokines were measured using RT-qPCR. The levels of cytokines in cell supernatants were determined by ELISA. The expression of cytochrome P450 1A1(CYP1A1) and forkhead box P3 (Foxp3) were measured by Western blotting. TolDCs were transferred to murine colitis model and the intestinal inflammation were evaluated. T-helper (Th) 17 cells and Treg in spleens and mesenteric lymph nodes (MLNs) were analyzed by flow cytometry. Results AhR activation in the DCs resulted in a lower expression of surface markers such as CD80, CD83, CD86, and pro-inflammatory cytokine production, and higher anti-inflammatory production (IL-1β, IL-23, and IL-12) compared to the control DCs. The surface dendrites in DCs were significantly reduced following AhR activation by FICZ. Such DCs with FICZ-mediated activation of AhR, namely tolDCs, inhibited CD4+ T cell proliferation and promoted Treg cell differentiation. Adoptive transfer of tolDCs to a TNBS-induced colitis mouse model significantly alleviated the severity of inflammation by decreasing the frequency of Th17 cells and increasing the frequency of Treg cells. Conclusions Activation of AhR in the DCs could induce tolDCs, and the transplantation of tolDCs may help in relieving intestinal inflammation and maintaining the Th17/Treg differentiation balance. Thus, our data suggest that AhR may be a potential therapeutic target for CD.