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Critical Role of Mast Cells and Peroxisome Proliferator–Activated Receptor γ in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo

Venkatesh L. Hegde, Udai P. Singh, Prakash S. Nagarkatti and Mitzi Nagarkatti
J Immunol June 1, 2015, 194 (11) 5211-5222; DOI: https://doi.org/10.4049/jimmunol.1401844
Venkatesh L. Hegde
*Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209; and
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Udai P. Singh
*Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209; and
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Prakash S. Nagarkatti
*Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209; and
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Mitzi Nagarkatti
*Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209; and
†Wm. Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, SC 29208
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Abstract

Cannabidiol (CBD) is a natural nonpsychotropic cannabinoid from marijuana (Cannabis sativa) with anti-epileptic and anti-inflammatory properties. Effect of CBD on naive immune system is not precisely understood. In this study, we observed that administering CBD into naive mice triggers robust induction of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) in the peritoneum, which expressed functional arginase 1, and potently suppressed T cell proliferation ex vivo. Furthermore, CBD-MDSC suppressed LPS-induced acute inflammatory response upon adoptive transfer in vivo. CBD-induced suppressor cells were comprised of CD11b+Ly6-G+Ly6-C+ granulocytic and CD11b+Ly6-G−Ly6-C+ monocytic subtypes, with monocytic MDSC exhibiting higher T cell–suppressive function. Induction of MDSC by CBD was markedly attenuated in Kit-mutant (KitW/W-v) mast cell–deficient mice. MDSC response was reconstituted upon transfer of wild-type bone marrow–derived mast cells in KitW/W-v mice, suggesting the key role of cKit (CD117) as well as mast cells. Moreover, mast cell activator compound 48/80 induced significant levels of MDSC in vivo. CBD administration in mice induced G-CSF, CXCL1, and M-CSF, but not GM-CSF. G-CSF was found to play a key role in MDSC mobilization inasmuch as neutralizing G-CSF caused a significant decrease in MDSC. Lastly, CBD enhanced the transcriptional activity of peroxisome proliferator-activated receptor γ in luciferase reporter assay, and PPAR-γ selective antagonist completely inhibited MDSC induction in vivo, suggesting its critical role. Together, the results suggest that CBD may induce activation of PPAR-γ in mast cells leading to secretion of G-CSF and consequent MDSC mobilization. CBD being a major component of Cannabis, our study indicates that marijuana may modulate or dysregulate the immune system by mobilizing MDSC.

Footnotes

  • This work was supported in whole or part by National Institutes of Health Grants K01DA034892 (to V.L.H.), P01AT003961, P20RR032684, R01AT006888, R01ES019313, and R01MH094755 and Veterans Affairs Merit Award 101BX001357 (to P.S.N. and M.N.).

  • Abbreviations used in this article:

    A2A
    adenosine receptor 2A
    Arg1
    arginase 1
    BADGE
    bisphenol A diglycidyl ether
    BM
    bone marrow
    CBD
    cannabidiol
    Gr
    granulocytic
    MDSC
    myeloid-derived suppressor cell
    Mo
    monocytic
    nor-NOHA
    Nω-hydroxy-nor-arginine
    PPAR
    peroxisome proliferator–activated receptor
    TG
    thioglycolate
    THC
    tetrahydrocannabinol
    WT
    wild-type.

  • Received July 22, 2014.
  • Accepted March 23, 2015.
  • Copyright © 2015 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 194 (11)
The Journal of Immunology
Vol. 194, Issue 11
1 Jun 2015
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Critical Role of Mast Cells and Peroxisome Proliferator–Activated Receptor γ in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo
Venkatesh L. Hegde, Udai P. Singh, Prakash S. Nagarkatti, Mitzi Nagarkatti
The Journal of Immunology June 1, 2015, 194 (11) 5211-5222; DOI: 10.4049/jimmunol.1401844

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Critical Role of Mast Cells and Peroxisome Proliferator–Activated Receptor γ in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo
Venkatesh L. Hegde, Udai P. Singh, Prakash S. Nagarkatti, Mitzi Nagarkatti
The Journal of Immunology June 1, 2015, 194 (11) 5211-5222; DOI: 10.4049/jimmunol.1401844
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