| Abstract |
Aryl hydrocarbon receptor (AhR), is a transcription factor and an environmental sensor that has been shown to regulate T cell differentiation. Interestingly, AhR ligands exert varying effects from suppression to exacerbation of inflammation through induction of Tregs and Th-17 cells, respectively. In the current study, we investigated whether the differential effects of AhR ligands on T cell differentiation are mediated by miRNA during delayed-type hypersensitivity (DTH) reaction against methylated Bovine Serum Albumin (mBSA). Treatment of C57BL/6 mice with TCDD attenuated mBSA-mediated DTH response, induced Tregs, decreased Th-17 cells, and caused upregulation of miRNA-132. TCDD caused an increase in several Treg subsets including inducible peripheral, natural thymic, and Th3 cells. Also, TCDD increased TGF-β and Foxp3 expression. In contrast, treating mice with FICZ exacerbated the DTH response, induced inflammatory Th17 cells, induced IL-17, and RORγ. Analysis of miRNA profiles from draining lymph nodes showed that miR-132 was upregulated in the TCDD group and downregulated in the FICZ group. Transfection studies revealed that miRNA-132 targeted High Mobility Group Box 1 (HMGB1). Downregulation of HMGB1 caused an increase in FoxP3+ Treg differentiation and suppression of Th-17 cells while upregulation of HMGB1 caused opposite effects. Moreover, TCDD was less effective in suppressing DTH response and induction of Tregs in mice that were deficient in miR-132. In summary, this study demonstrates that TCDD and FICZ have divergent effects on DTH response and T cell differentiation, which is mediated through, at least in part, regulation of miRNA-132 that targets HMGB1.
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| MeSH term(s) |
Animals ; Basic Helix-Loop-Helix Transcription Factors/agonists ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Carbazoles/toxicity ; Cell Differentiation/drug effects ; Cells, Cultured ; Cytokines/genetics ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; HMGB1 Protein/genetics ; HMGB1 Protein/metabolism ; Hypersensitivity, Delayed/genetics ; Hypersensitivity, Delayed/immunology ; Hypersensitivity, Delayed/metabolism ; Hypersensitivity, Delayed/prevention & control ; Ligands ; Mice, Inbred C57BL ; Mice, Knockout ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Phenotype ; Polychlorinated Dibenzodioxins/toxicity ; Receptors, Aryl Hydrocarbon/agonists ; Receptors, Aryl Hydrocarbon/metabolism ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Th17 Cells/drug effects ; Th17 Cells/immunology ; Th17 Cells/metabolism ; Mice |
| Chemical Substances |
6-formylindolo(3,2-b)carbazole ; Ahr protein, mouse ; Basic Helix-Loop-Helix Transcription Factors ; Carbazoles ; Cytokines ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; HMGB1 Protein ; HMGB1 protein, mouse ; Ligands ; MIRN132 microRNA, mouse ; MicroRNAs ; Polychlorinated Dibenzodioxins ; Receptors, Aryl Hydrocarbon |
| Language |
English |
| Publishing date |
2021-02-19 |
| Publishing country |
Switzerland |
| Document type |
Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID |
2606827-8 |
| ISSN |
1664-3224 ; 1664-3224 |
| ISSN (online) |
1664-3224 |
| ISSN |
1664-3224 |
| DOI |
10.3389/fimmu.2021.635903 |
| Database |
MEDical Literature Analysis and Retrieval System OnLINE |
