Activation of CB1R Promotes Lipopolysaccharide-Induced IL-10 Secretion by Monocytic Myeloid-Derived Suppressive Cells and Reduces Acute Inflammation and Organ Injury

Jérémie Joffre, Che-Chung Yeh, Erika Wong, Mayuri Thete, Fengyun Xu, Ivana Zlatanova, Elliot Lloyd, Lester Kobzik, Matthieu Legrand, and Judith Hellman

The Journal of Immunology, 2020, 204: 1–20.

doi : 10.4049/jimmunol.2000213

 

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 (CB1R) 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 CB1R. These data have implications for acute and chronic conditions that are driven by dysregulated inflammation, such as sepsis, and raise the possibility that CB1R-signaling may constitute a novel target for inflammatory disorders.

Since ancient times, people have made use of plants containing phytocannabinoids (1) for therapeutic, recreational, and religious purposes (2). In the United States, cannabis was widely used and referenced in the Pharmacopoeia from 1850 to the early 20th century. However, in 1937, federal restrictions were put in place that made it difficult to perform studies on cannabinoids in human health and disease (3). The endocannabinoid system includes cannabinoid receptors (CBRs) and vanilloid receptors. CBRs are a group of evolutionarily conserved G protein– coupled receptors (GPCRs) (4, 5) that are expressed by primitive vertebrates as well as more advanced species, including humans, and in numerous tissues and cellular subsets (6). CBRs recognize heterologous cannabinoids, including phytocannabinoids such as D(9)-tetrahydrocannabinol (D9-THC), and endocannabinoids such as anandamide (AEA) or 2-arachido-noylglycerol (2-AG). Cannabinoids are putative ligands for CBRs type 1 (CB1R) or 2 (CB2R) and additional GPCRs, including GPR18, GPR119, and GPR55 (7, 8), as well as ligand-gated ion-channels such as the transient receptor-potential vanilloid-1 (TRPV1) (9, 10). CBRs and vanilloid receptors are expressed in the nervous system, as well as in a variety of other tissues and cells, including dendritic cells, monocytes/ macrophages, T cells and B cells (11, 12). This finding suggests that their function in the body may extend well beyond a role in neuronal function.

A number of immune cell subsets express CBRs, and cannabinoids have been reported to affect cytokine production in immune cells. However, the vast majority of these publications studied cells in vitro or ex vivo (13), and there is little information on the effects of cannabinoids in vivo in acute inflammation or on the regulation of the endocannabinoid system during inflammatory illnesses such as sepsis.

In the current studies, we demonstrate that D9-THC has strong and sustained anti-inflammatory properties in mice with acute inflammation and decipher its mechanisms of action. Our results show that in endotoxemic mice, D9-THC increases the secretion of the antiinflammatory cytokine IL-10 by monocytic myeloid-derived suppressive cells (Mo-MDSCs) in a CB1R-dependent manner. D9-THC also dramatically reduces levels of proinflammatory mediators, immune cell activation, and potentially alleviates organ injury.

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