Critical role of mast cells and peroxisome proliferator-activated receptor gamma (PPARγ) in the induction of myeloid-derived suppressor cells by marijuana cannabidiol in vivo

摘要

Cannabidiol (CBD) is a natural non-psychotropic cannabinoid from marijuana (Cannabis sativa) with anti-epileptic and anti-inflammatory properties. Effect of CBD on naïve immune system is not precisely understood. In this study, we observed that administering CBD into naïve mice triggers robust induction of CD11b⁺Gr-1⁺ MDSC in the peritoneum, which expressed functional Arg1, and potently suppressed T cell proliferation ex vivo. Further, 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 WT 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 PPARγ in luciferase reporter assay, and PPARγ selective antagonist completely inhibited MDSC induction in vivo suggesting its critical role. Together, the results suggest that CBD may induce activation of PPARγ 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.