Activation of CB1R Promotes Lipopolysaccharide-Induced IL-10 Secretion by Monocytic Myeloid-Derived Suppressive Cells and Reduces Acute Inflammation and Organ Injury
Abstract
Cannabis sativa and its principal components, D9-tetrahydrocannabinol (D9-THC) and cannabidiol, are increasingly being used to treat a variety of medical problems, including inflammatory conditions. Although studies suggest that the endocannabinoid system has immunomodulatory properties, there remains a paucity of information on the effects of cannabinoids on immunity and on outcomes of infection and injury. We investigated the effects and mechanism(s) of action of cannabinoid receptor agonists, including D9-THC, on inflammation and organ injury in endotoxemic mice. Administration of D9-THC caused a dramatic early upregulation of plasma IL-10 levels, reduced plasma IL-6 and CCL-2 levels, led to better clinical status, and attenuated organ injury in endotoxemic mice. The anti-inflammatory effects of D9-THC in endotoxemic mice were reversed by a cannabinoid receptor type 1 (CB 1 R) inverse agonist (SR141716), and by clodronate-induced myeloid-cell depletion, but not by genetic invalidation or blockade of other putative D9-THC receptors, including cannabinoid receptor type 2, TRPV1, GPR18, GPR55, and GPR119. Although D9-THC administration reduced the activation of several spleen immune cell subsets, the anti-inflammatory effects of D9-THC were preserved in splenectomized endotoxemic mice. Finally, using IL-10-GFP reporter mice, we showed that blood monocytic myeloid-derived suppressive cells mediate the D9-THC-induced early rise in circulating IL-10. These results indicate that D9-THC potently induces IL-10, while reducing proinflammatory cytokines, chemokines, and related organ injury in endotoxemic mice via the activation of CB 1 R. These data have implications for acute and chronic conditions that are driven by dysregulated inflammation, such as sepsis, and raise the possibility that CB 1 R-signaling may constitute a novel target for inflammatory disorders.
Keywords
ACEA
arachidonoyl-29-chloroethylamide ACN
acetonitrile ACPA
arachidonoyl cyclopropylamide AEA
anandamide 2A-G
2-arachidonoyl glycerol CBR
cannabinoid receptor CB 1 R
CBR type 1 CB 2 R
CBR type 2 GPCR
G protein-coupled receptor Mo-MDSC
monocytic myeloidderived suppressive cell MSS
murine sepsis score MtBE
methyl tert-butyl ether NADA
N-arachidonoyl dopamine D9-THC
D(9)-tetrahydrocannabinol Treg
regulatory T cell TRVP1
transient receptor-potential vanilloid-1 UCSF
University of California
San Francisco WT
wild-type C57BL/6J
arachidonoyl-29-chloroethylamide
ACN
acetonitrile
ACPA
arachidonoyl cyclopropylamide
AEA
anandamide
2A-G
2-arachidonoyl glycerol
CBR
cannabinoid receptor
CB 1 R
CBR type 1
CB 2 R
CBR type 2
GPCR
G protein-coupled receptor
Mo-MDSC
monocytic myeloidderived suppressive cell
MSS
murine sepsis score
MtBE
methyl tert-butyl ether
NADA
N-arachidonoyl dopamine
D9-THC
D(9)-tetrahydrocannabinol
Treg
regulatory T cell
TRVP1
transient receptor-potential vanilloid-1
UCSF
San Francisco
WT
Domains
Life Sciences [q-bio]| Origin | Publisher files allowed on an open archive |
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