AhR Activation by TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin) Attenuates Pertussis Toxin-Induced Inflammatory Responses by Differential Regulation of Tregs and Th17 Cells Through Specific Targeting by microRNA

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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.

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