Targeted deletion of the aryl hydrocarbon receptor in dendritic cells prevents thymic atrophy in response to dioxin.

Abstract

In nearly every species examined, administration of the persistent environmental pollutant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD) causes profound immune suppression and thymic atrophy in an aryl hydrocarbon receptor (AhR) dependent manner. Moreover, TCDD alters the development and differentiation of thymocytes, resulting in decreases in the relative proportion and absolute number of double positive (DP, CD4+CD8+) thymocytes, as well as a relative enrichment in the relative proportion and absolute number of double negative (DN, CD4-CD8-) and single-positive (SP) CD4+CD8- and CD4-CD8+ thymocytes. Previous studies suggested that the target for TCDD-induced thymic atrophy resides within the hemopoietic compartment and implicated apoptosis, proliferation arrest of thymic progenitors, and emigration of DN thymocytes to the periphery as potential contributors to TCDD-induced thymic atrophy. However, the precise cellular and molecular mechanisms involved remain largely unknown. Our results show that administration of 10 µg/kg TCDD and 8 mg/kg 2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester (ITE) induced AhR-dependent thymic atrophy in mice on day 7, whereas 100 mg/kg indole 3-carbinol (I3C) did not. Though our studies demonstrate that TCDD triggers a twofold increase in the frequency of apoptotic thymocytes, TCDD-induced thymic atrophy is not dependent on Fas-FasL interactions, and thus, enhanced apoptosis is unlikely to be a major mechanistic contributor. Finally, our results show that activation of the AhR in CD11c+ dendritic cells is directly responsible for TCDD-induced alterations in the development and differentiation of thymocytes, which results in thymic atrophy. Collectively, these results suggest that CD11c+ dendritic cells play a critical role in mediating TCDD-induced thymic atrophy and disruption of T lymphocyte development and differentiation in the thymus.

• Authors: Celine A Beamer, Joanna M Kreitinger, Shelby L Cole, David M Shepherd
• Journal: Archives of toxicology (Arch Toxicol) Vol. 93 Issue 2 Pg. 355-368 (02 2019) ISSN: 1432-0738 [Electronic] Germany
• PMID: 30499018 (Publication Type: Journal Article)

Chemical References

• 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester
• AHR protein, human
• Ahr protein, mouse
• Basic Helix-Loop-Helix Transcription Factors
• Fas Ligand Protein
• Fas protein, mouse
• Fasl protein, mouse
• Indoles
• Polychlorinated Dibenzodioxins
• Receptors, Aryl Hydrocarbon
• Thiazoles
• fas Receptor
• indole-3-carbinol

Topics

• Animals
• Apoptosis (drug effects)
• Atrophy (chemically induced, genetics, prevention & control)
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Dendritic Cells (drug effects, pathology)
• Dose-Response Relationship, Drug
• Fas Ligand Protein (metabolism)
• Female
• Indoles (administration & dosage, pharmacology, toxicity)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Polychlorinated Dibenzodioxins (toxicity)
• Receptors, Aryl Hydrocarbon (genetics, metabolism)
• Thiazoles (administration & dosage, toxicity)
• Thymus Gland (drug effects, pathology)
• fas Receptor (metabolism)