Critical Role of Mast Cells and Peroxisome Proliferator-Activated Receptor γ in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo.
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.
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209; and.
Venkatesh L
VL
Hegde
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209; and.
Udai P
UP
Singh
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209; and.
Prakash S
PS
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 mnagark@uscmed.sc.edu.
Mitzi
M
Nagarkatti
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001119:Arginase / Q000096:biosynthesis; D039481:CD11b Antigen / Q000378:metabolism; D002185:Cannabidiol / Q000494:pharmacology*; D002188:Cannabis / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D008407:Mast Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics*; D019707:Receptors, Chemokine / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D015533:Transcriptional Activation / Q000235:genetics; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D039481:CD11b Antigen; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C503133:Gr-1 protein, mouse; D047495:PPAR gamma; D019707:Receptors, Chemokine; D016179:Granulocyte Colony-Stimulating Factor; D002185:Cannabidiol; D003189:p-Methoxy-N-methylphenethylamine; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C544448:Arg1 protein, mouse; D001119:Arginase