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2015 ; 194
(11
): 5211-22
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Critical Role of Mast Cells and Peroxisome Proliferator-Activated Receptor ? in
the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In
Vivo
#MMPMID25917103
Hegde VL
; Singh UP
; Nagarkatti PS
; Nagarkatti M
J Immunol
2015[Jun]; 194
(11
): 5211-22
PMID25917103
show ga
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 ? in luciferase reporter assay, and PPAR-?
selective antagonist completely inhibited MDSC induction in vivo, suggesting its
critical role. Together, the results suggest that CBD may induce activation of
PPAR-? 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.