Original Research ARTICLE
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
- 1University of South Carolina, United States
- 2School of Medicine Columbia, University of South Carolina, United States
The Aryl Hydrocarbon Receptor (AhR) is a ligand activated transcription factor implicated in the regulation of 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 heightened inflammatory response. The role of AhR in the regulation of PTX-mediated inflammation has not been previously studied. In the current study, we investigated 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 twice i.p. with PTX and treated with TCDD or vehicle (VEH). PTX+VEH group had elevated levels of pro-inflammatory cytokines (IL-17A, IL-6, and IFNγ) in serum and increased proportions of CD4+ Th1 and Th17 cells in spleens. In contrast, PTX+TCDD group had 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 PTX+VEH group. PTX+TCDD treated mice also had elevated levels of IL-10, and TFG-, potent anti-inflammatory cytokines. microRNAs (miRs) analysis of CD4+ T cells from the spleens of PTX+TCDD treated mice revealed significant alterations in their expression and several of these miRs targeted cytokines and signaling molecules involved in inflammation. Specifically, PTX+TCDD group had significantly enhanced expression of miR-3082-5p that targeted IL-17, and decreased expression of miR-1224-5p, which targeted FoxP3. Transfection studies with these miR mimics and inhibitors confirmed the specificity of the target genes. Together, 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. These studies also suggest that AhR activation may serve as a treatment modality to suppress heightened inflammation induced during B. pertussis infection.
Keywords: Aryl hydrocarbon receptor (AhR), Pertussis Toxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin, Immunosuppression, Inflammation, microRNA
Received: 25 Jun 2019;
Accepted: 26 Sep 2019.
Copyright: © 2019 Al-Ghezi, Singh, Mehrpouya, Nagarkatti and PRAKASH. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. NAGARKATTI S. PRAKASH, School of Medicine Columbia, University of South Carolina, Columbia, 29209, South Carolina, United States, email@example.com