AhR Activation Leads to Alterations in the Gut Microbiome with Consequent Effect on Induction of Myeloid Derived Suppressor Cells in a CXCR2-Dependent Manner.

Wurood Hantoosh Neamah,Philip Brandon Busbee,Mitzi Nagarkatti,Hasan Alghetaa,Prakash Nagarkatti,Osama A Abdulla

doi:10.3390/ijms21249613

Wurood Hantoosh Neamah, Philip Brandon Busbee + Show 4 more

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https://doi.org/10.3390/ijms21249613

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Abstract

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR and a known carcinogen. While AhR activation by TCDD leads to significant immunosuppression, how this translates into carcinogenic signal is unclear. Recently, we demonstrated that activation of AhR by TCDD in naïve C57BL6 mice leads to massive induction of myeloid derived-suppressor cells (MDSCs). In the current study, we investigated the role of the gut microbiota in TCDD-mediated MDSC induction. TCDD caused significant alterations in the gut microbiome, such as increases in Prevotella and Lactobacillus, while decreasing Sutterella and Bacteroides. Fecal transplants from TCDD-treated donor mice into antibiotic-treated mice induced MDSCs and increased regulatory T-cells (Tregs). Injecting TCDD directly into antibiotic-treated mice also induced MDSCs, although to a lesser extent. These data suggested that TCDD-induced dysbiosis plays a critical role in MDSC induction. Interestingly, treatment with TCDD led to induction of MDSCs in the colon and undetectable levels of cysteine. MDSCs suppressed T cell proliferation while reconstitution with cysteine restored this response. Lastly, blocking CXC chemokine receptor 2 (CXCR2) impeded TCDD-mediated MDSC induction. Our data demonstrate that AhR activation by TCDD triggers dysbiosis which, in turn, regulates, at least in part, induction of MDSCs.

Highlights

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR and a known carcinogen
TCDD is a well characterized high affinity ligand for AhR; we used TCDD to investigate how AhR activation alters the gut microbiota. 16S rRNA sequencing with the Illumina MiSeq platform was performed on feces from the following groups: wild-type mice, mice treated with corn oil, and mice given 10 μg/kg intraperitoneal (i.p.) injections of TCDD
Data collected from sequencing showed that vehicle or TCDD-treated mice had decreased alpha diversity when compared with naïve controls, which was assessed by Chao1 rarefaction measurement (Figure 1A)

Summary

Introduction

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR and a known carcinogen. Mice treated orally with TCDD developed tolerance to ovalbumin (OVA) and showed suppression in the humoral immune response in the epithelial cells of the lumen, as well as serum and fecal samples [8]. In these same studies, alterations of other immune cells (e.g., CD4+, CD8+, CD19+, and CD103+MHCII+CD11c+) by TCDD occurred only in the gut-specific draining lymph node (MLN). Using fecal material transfer (FMT) experiments, we found that MDSC induction by TCDD was dependent, at least in part, on the gut microbiota

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