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

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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 (Kit(W/W-v)) mast cell-deficient mice. MDSC response was reconstituted upon transfer of wild-type bone marrow-derived mast cells in Kit(W/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.

Original languageEnglish (US)
Pages (from-to)5211-22
Number of pages12
JournalJournal of Immunology
Volume194
Issue number11
DOIs
StatePublished - Jun 1 2015

Keywords

  • Animals
  • Anti-Inflammatory Agents
  • Arginase
  • CD11b Antigen
  • Cannabidiol
  • Cannabis
  • Cell Proliferation
  • Chemokine CXCL1
  • Female
  • Granulocyte Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Macrophage Colony-Stimulating Factor
  • Mast Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells
  • PPAR gamma
  • Receptors, Chemokine
  • T-Lymphocytes
  • Transcriptional Activation
  • p-Methoxy-N-methylphenethylamine
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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