| First Author | Joffre J | Year | 2020 |
| Journal | J Immunol | Volume | 204 |
| Issue | 12 | Pages | 3339-3350 |
| PubMed ID | 32385136 | Mgi Jnum | J:291565 |
| Mgi Id | MGI:6445002 | Doi | 10.4049/jimmunol.2000213 |
| Citation | Joffre J, et al. (2020) Activation of CB1R Promotes Lipopolysaccharide-Induced IL-10 Secretion by Monocytic Myeloid-Derived Suppressive Cells and Reduces Acute Inflammation and Organ Injury. J Immunol 204(12):3339-3350 |
| abstractText | Cannabis sativa and its principal components, Delta9-tetrahydrocannabinol (Delta9-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 Delta9-THC, on inflammation and organ injury in endotoxemic mice. Administration of Delta9-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 Delta9-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 Delta9-THC receptors, including cannabinoid receptor type 2, TRPV1, GPR18, GPR55, and GPR119. Although Delta9-THC administration reduced the activation of several spleen immune cell subsets, the anti-inflammatory effects of Delta9-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 Delta9-THC-induced early rise in circulating IL-10. These results indicate that Delta9-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. |
