Abstract
The Aryl Hydrocarbon Receptor (AhR) is a transcription factor that, when activated by ligand-binding, has been shown to regulate the immune response. Pertussis Toxin (PTX) is a virulence factor found in Bordetella pertussis, a human respiratory pathogen that causes whooping cough. PTX promotes colonization and disease promotion by triggering a heightened inflammatory response. The role of AhR in the regulation of PTX-mediated inflammation has not previously been studied. In the current study, we investigate if AhR activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a well characterized ligand, can attenuate PTX-mediated systemic inflammation. To that end, C57BL/6 mice were injected intraperitoneally (IP) with PTX twice and treated with TCDD or vehicle (VEH). The PTX+VEH group showed elevated levels of pro-inflammatory cytokines (IL-17A, IL-6, and IFNγ) in serum and increased proportions of CD4+ Th1 and Th17 cells in their spleens. In contrast, the PTX+TCDD group showed significantly lower levels of these inflammatory cytokines and decreased proportions of Th1 and Th17 cells, but increased proportions of Th2 and FoxP3+Tregs when compared to the PTX+VEH group. PTX+TCDD treated mice also showed elevated levels of IL-10, and TFG-b, potent anti-inflammatory cytokines. MicroRNAs (miRs) analysis of CD4+ T cells from the spleens of the PTX+TCDD treated mice revealed significant alterations in their expression and several of these miRs targeted cytokines and signaling molecules involved in inflammation. Specifically, the PTX+TCDD group had a significantly enhanced expression of miR-3082-5p that targeted IL-17, and a decreased expression of miR-1224-5p, which targeted FoxP3. Transfection studies with these miR mimics and inhibitors confirmed the specificity of the target genes. The current study suggests that AhR activation by TCDD suppresses PTX-induced inflammation through miR regulation that triggers reciprocal polarization of Tregs and Th17 cells and also suggests that AhR activation may serve as a treatment modality to suppress heightened inflammation induced during B. pertussis infection.
Highlights
TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin), known as dioxin, is a polyhalogenated aromatic hydrocarbon (Birnbaum, 1994)
We investigated whether aryl hydrocarbon receptor (AhR) activation by TCDD can attenuate Pertussis Toxin (PTX)-induced inflammation in mice and if so, whether such anti-inflammatory action is mediated by miRNAs
We investigated the effect of AhR activation by TCDD on the PTX-mediated inflammatory response in C57BL/6 mice
Summary
TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin), known as dioxin, is a polyhalogenated aromatic hydrocarbon (Birnbaum, 1994). Studies have shown that in addition to its toxicological functions, AhR is known to regulate the immune response, through affecting T cell differentiation (Quintana and Sherr, 2013; Gutierrez-Vazquez and Quintana, 2018). The evidence linking environmental chemical contaminants like dioxin and miRNAs functions to human diseases is rapidly growing (Hou et al, 2012) It is not yet clear how AhR activation by TCDD alters miRNAs or the possibility that TCDD-induced miRNAs may control mRNA that regulate inflammation. We investigated whether AhR activation by TCDD can attenuate PTX-induced inflammation in mice and if so, whether such anti-inflammatory action is mediated by miRNAs. Our studies demonstrate that TCDD does alter the expression of several miRNAs that target various cytokine and transcription factors in T cells, leading to the suppression of PTX-mediated inflammation
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