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.

Polyphenols and Cannabidiol Modulate Transcriptional Regulation of Th1/Th2 Inflammatory Genes Related to Canine Atopic Dermatitis

“…The data in literature related to in vitro and in vivo effects of polyphenols and cannabidiol on Th1 homing cytokines support our results ( 40 , 41 ). In this regard, ccl2 expression was inhibited in human keratinocytes and skin treated with polyphenols in vitro and in vivo ( 42 , 43 ); in murine monocyte cell lines, ccl2 blunting was observed after the luteolin treatment ( 44 ) and furthermore, piceatannol and cannabidiol are both capable of inhibiting ccl2 expression in activated macrophages in vitro ( 45 , 46 ).…”

“…They represent new target molecules for AD therapy, together with TSLP, IL-4, and IL-31, that could dampen Th2 responses regulating the immune cell proliferation and stimulation of sensory cutaneous neurons to transmit itch sensation (38,39). The data in literature related to in vitro and in vivo effects of polyphenols and cannabidiol on Th1 homing cytokines support our results (40,41). In this regard, ccl2 expression was inhibited in human keratinocytes and skin treated with polyphenols in vitro and in vivo (42,43); in murine monocyte cell lines, ccl2 blunting was observed after the luteolin treatment (44) and furthermore, piceatannol and cannabidiol are both capable of inhibiting ccl2 expression in activated macrophages in vitro (45,46).…”

The Neuroimmunology of Chronic Pain: From Rodents to Humans

“…While sensory neurons have the capacity to powerfully regulate immune responses (Pinho-Ribeiro et al, 2017), it is unclear whether CB1R expression by sensory neurons or macrophages regulates inflammation after injury (Amaya et al, 2006). This is an important distinction, as the anti-inflammatory effects of CB1R through expression on immune cells is a recent finding (Cinar et al, 2017;Joffre et al, 2020).…”

The Impact of CB1 Receptor on Inflammation in Skeletal Muscle Cells

“…11,13 Thus, cannabinoid systems emerge as major factors in inflammatory regulation processes. 14,15 Targeting components, specifically the CB1 receptor, may aid in developing possible treatments for people with inflammatory diseases and related disorders, including insulin resistance in type II diabetes. 12 Inflammation plays a key role in the pathogenesis of disorders involving skeletal muscle failure.…”