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Open Access

AhR Activation Leads to Massive Mobilization of Myeloid-Derived Suppressor Cells with Immunosuppressive Activity through Regulation of CXCR2 and MicroRNA miR-150-5p and miR-543-3p That Target Anti-Inflammatory Genes

Wurood Hantoosh Neamah, Narendra P. Singh, Hasan Alghetaa, Osama A. Abdulla, Saurabh Chatterjee, Philip B. Busbee, Mitzi Nagarkatti and Prakash Nagarkatti
J Immunol September 6, 2019, ji1900291; DOI: https://doi.org/10.4049/jimmunol.1900291
Wurood Hantoosh Neamah
*Department of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, SC 29208; and
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Narendra P. Singh
*Department of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, SC 29208; and
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Hasan Alghetaa
*Department of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, SC 29208; and
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Osama A. Abdulla
*Department of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, SC 29208; and
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Saurabh Chatterjee
†Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208
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Philip B. Busbee
*Department of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, SC 29208; and
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Mitzi Nagarkatti
*Department of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, SC 29208; and
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Prakash Nagarkatti
*Department of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, SC 29208; and
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Key Points

  • AhR activation leads to induction of MDSCs with immunosuppressive activity.

  • AhR-mediated induction of MDSCs is regulated by microRNA that target CXCR2.

Abstract

The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant, is a potent ligand for aryl hydrocarbon receptor (AhR). In the current study, we made an exciting observation that naive C57BL/6 mice that were exposed i.p. to TCDD showed massive mobilization of myeloid-derived suppressor cells (MDSCs) in the peritoneal cavity. These MDSCs were highly immunosuppressive and attenuated Con A–induced hepatitis upon adoptive transfer. TCDD administration in naive mice also led to induction of several chemokines and cytokines in the peritoneal cavity and serum (CCL2, CCL3, CCL4, CCL11, CXCL1, CXCL2, CXCL5, CXCL9, G-CSF, GM-CSF, VEGF, and M-CSF) and chemokine receptors on MDSCs (CCR1, CCR5, and CXCR2). Treatment with CXCR2 or AhR antagonist in mice led to marked reduction in TCDD-induced MDSCs. TCDD-induced MDSCs had high mitochondrial respiration and glycolytic rate and exhibited differential microRNA (miRNA) expression profile. Specifically, there was significant downregulation of miR-150-5p and miR-543-3p. These two miRNAs targeted and enhanced anti-inflammatory and MDSC-regulatory genes, including IL-10, PIM1, ARG2, STAT3, CCL11 and its receptors CCR3 and CCR5 as well as CXCR2. The role of miRs in MDSC activation was confirmed by transfection studies. Together, the current study demonstrates that activation of AhR in naive mice triggers robust mobilization of MDSCs through induction of chemokines and their receptors and MDSC activation through regulation of miRNA expression. AhR ligands include diverse compounds from environmental toxicants, such as TCDD, that are carcinogenic to dietary indoles that are anti-inflammatory. Our studies provide new insights on how such ligands may regulate health and disease through induction of MDSCs.

Footnotes

  • This work was supported by funding sources from the National Institutes of Health (R01ES019313, R01MH094755, R01AI123947, R01AI129788, P01AT003961, P20GM103641, and R01AT006888) and the Ministry of Higher Education and Scientific Research, Iraq.

  • The microarray data presented in this article have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE134337.

  • The online version of this article contains supplemental material.

  • Received March 12, 2019.
  • Accepted July 30, 2019.
  • Copyright © 2019 by The American Association of Immunologists, Inc.

This article is distributed under The American Association of Immunologists, Inc., Reuse Terms and Conditions for Author Choice articles.

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The Journal of Immunology: 206 (2)
The Journal of Immunology
Vol. 206, Issue 2
15 Jan 2021
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AhR Activation Leads to Massive Mobilization of Myeloid-Derived Suppressor Cells with Immunosuppressive Activity through Regulation of CXCR2 and MicroRNA miR-150-5p and miR-543-3p That Target Anti-Inflammatory Genes
Wurood Hantoosh Neamah, Narendra P. Singh, Hasan Alghetaa, Osama A. Abdulla, Saurabh Chatterjee, Philip B. Busbee, Mitzi Nagarkatti, Prakash Nagarkatti
The Journal of Immunology September 6, 2019, ji1900291; DOI: 10.4049/jimmunol.1900291

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AhR Activation Leads to Massive Mobilization of Myeloid-Derived Suppressor Cells with Immunosuppressive Activity through Regulation of CXCR2 and MicroRNA miR-150-5p and miR-543-3p That Target Anti-Inflammatory Genes
Wurood Hantoosh Neamah, Narendra P. Singh, Hasan Alghetaa, Osama A. Abdulla, Saurabh Chatterjee, Philip B. Busbee, Mitzi Nagarkatti, Prakash Nagarkatti
The Journal of Immunology September 6, 2019, ji1900291; DOI: 10.4049/jimmunol.1900291
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