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

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

doi:10.3390/ijms21249613

Open AccessArticle

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

by

Wurood Hantoosh Neamah

,

Philip Brandon Busbee

,

Hasan Alghetaa

,

Osama A. Abdulla

,

Mitzi Nagarkatti

and

Prakash Nagarkatti

^*

Department of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2020, 21(24), 9613; https://doi.org/10.3390/ijms21249613

Submission received: 3 November 2020 / Revised: 27 November 2020 / Accepted: 12 December 2020 / Published: 17 December 2020

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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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.

Keywords: 2,3,7,8-tetrachlorodibenzo-p-dioxin; aryl hydrocarbon receptor; microbiome; myeloid-derived suppressor cell; CXCR2

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MDPI and ACS Style

Neamah, W.H.; Busbee, P.B.; Alghetaa, H.; Abdulla, O.A.; Nagarkatti, M.; Nagarkatti, P. AhR Activation Leads to Alterations in the Gut Microbiome with Consequent Effect on Induction of Myeloid Derived Suppressor Cells in a CXCR2-Dependent Manner. Int. J. Mol. Sci. 2020, 21, 9613. https://doi.org/10.3390/ijms21249613

AMA Style

Neamah WH, Busbee PB, Alghetaa H, Abdulla OA, Nagarkatti M, Nagarkatti P. AhR Activation Leads to Alterations in the Gut Microbiome with Consequent Effect on Induction of Myeloid Derived Suppressor Cells in a CXCR2-Dependent Manner. International Journal of Molecular Sciences. 2020; 21(24):9613. https://doi.org/10.3390/ijms21249613

Chicago/Turabian Style

Neamah, Wurood Hantoosh, Philip Brandon Busbee, Hasan Alghetaa, Osama A. Abdulla, Mitzi Nagarkatti, and Prakash Nagarkatti. 2020. "AhR Activation Leads to Alterations in the Gut Microbiome with Consequent Effect on Induction of Myeloid Derived Suppressor Cells in a CXCR2-Dependent Manner" International Journal of Molecular Sciences 21, no. 24: 9613. https://doi.org/10.3390/ijms21249613

APA Style

Neamah, W. H., Busbee, P. B., Alghetaa, H., Abdulla, O. A., Nagarkatti, M., & Nagarkatti, P. (2020). AhR Activation Leads to Alterations in the Gut Microbiome with Consequent Effect on Induction of Myeloid Derived Suppressor Cells in a CXCR2-Dependent Manner. International Journal of Molecular Sciences, 21(24), 9613. https://doi.org/10.3390/ijms21249613

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

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