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

• Published in: The Journal of immunology (1950) Vol. 204; no. 12; pp. 3339 - 3350
• Main Authors: Joffre, Jérémie, Yeh, Che-Chung, Wong, Erika, Thete, Mayuri, Xu, Fengyun, Zlatanova, Ivana, Lloyd, Elliot, Kobzik, Lester, Legrand, Matthieu, Hellman, Judith
• Format: Journal Article
• Language: English
• Published: Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists 15-06-2020; AAI
• Subjects: Innate Immunity and Inflammation; Life Sciences; anandamide 2A-G; transient receptor-potential vanilloid-1; N-arachidonoyl dopamine D9-THC; University of California; G protein-coupled receptor Mo-MDSC; ACPA; D-tetrahydrocannabinol; Mo-MDSC; methyl tert-butyl ether; acetonitrile; AEA; anandamide; arachidonoyl cyclopropylamide; monocytic myeloidderived suppressive cell MSS; 2-arachidonoyl glycerol; ACEA; CB 2 R; arachidonoyl cyclopropylamide AEA; methyl tert-butyl ether NADA; CBR type 1; arachidonoyl-29-chloroethylamide; CBR type 2; monocytic myeloidderived suppressive cell; D9-THC; GPCR; TRVP1; UCSF; acetonitrile ACPA; wild-type C57BL/6J; cannabinoid receptor; CBR; NADA; murine sepsis score MtBE; murine sepsis score; WT; D-tetrahydrocannabinol Treg; transient receptor-potential vanilloid-1 UCSF; 2A-G; G protein-coupled receptor; N-arachidonoyl dopamine; regulatory T cell TRVP1; CB 1 R; Treg; regulatory T cell; ACN; MSS; arachidonoyl-29-chloroethylamide ACN; MtBE; CBR type 1 CB 2 R; San Francisco; 2-arachidonoyl glycerol CBR; San Francisco WT; cannabinoid receptor CB 1 R; CBR type 2 GPCR
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2000213

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.