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 Loyd; Lester Kobzik; Matthieu Legrand; Judith Hellman

doi:10.4049/jimmunol.2000213

Key Points

Δ9-THC increases IL-10 and reduces IL-6 and CCL2 in endotoxemic mice via CB₁R.
Δ9-THC decreases lung inflammation and organ injury in endotoxemic mice.
Monocytic-MDSCs mediate Δ9-THC–induced IL-10 upregulation in endotoxemic mice.

Abstract

Cannabis sativa and its principal components, Δ9-tetrahydrocannabinol (Δ9-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 Δ9-THC, on inflammation and organ injury in endotoxemic mice. Administration of Δ9-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 Δ9-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 Δ9-THC receptors, including cannabinoid receptor type 2, TRPV1, GPR18, GPR55, and GPR119. Although Δ9-THC administration reduced the activation of several spleen immune cell subsets, the anti-inflammatory effects of Δ9-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 Δ9-THC–induced early rise in circulating IL-10. These results indicate that Δ9-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.

Footnotes

This work was supported by National Institutes of Health (NIH) National Institute of General Medical Sciences Grant R01GM132379 (to J.H.), the University of California, San Francisco (UCSF) Department of Anesthesia and Perioperative Care (to J.H.), a fellowship from the Société de Réanimation de Langue Française (to J.J.), and the Amicale des Anciens Internes en Medicine des Hopitaux de Paris and Assistance Publique, Hopitaux de Paris (to J.J.). The UCSF Flow Cytometry Facility acknowledges Diabetes Research Center Grant NIH P30 DK063720.
The online version of this article contains supplemental material.