Suppression of CpG-ODN-mediated IFNα and TNFα response in human plasmacytoid dendritic cells (pDC) by cannabinoid receptor 2 (CB2)-specific agonists

Abstract

Plasmacytoid dendritic cells (pDC) compose 0.2-0.5% of circulating leukocytes but play a significant role in mounting host immune responses. Elevated and chronic activation of pDC are implicated in autoimmune disease like systemic lupus erythematosus and rheumatoid arthritis. Δ 9tetrahydrocannabinol (THC) is a well characterized cannabinoid with potent anti-inflammatory activity, but acceptance of THC as a treatment for autoimmune disorders has been hindered due to psychotropic activity. The psychotropic effects of THC are mediated through cannabinoid receptor 1 ( CB1) expressed in the central nervous system while the immunomodulatory effects of THC result from THC binding to CB1 and CB2 on immune cells. Synthetic CB2-selective agonists have been developed to explore immune modulation by cannabinoids in the absence of psychotropic effects. The goal of these studies was to determine if the CB2-selective agonists, JWH-015 and JWH-133, have comparable efficacy to THC in modulating IFNα and TNFα responses by primary human pDC. Treatment with JWH-133 and JWH-015 inhibited CpG-induced IFNα and TNFα responses by pDC. Further, the phosphorylation of IRF7, TBK1, NFκB, and IKKγ, key events in pDC activation, were suppressed by THC, JWH-133, and JWH-015. Likewise, the phosphorylation of AKT at the S473 and T308 residues were differentially modulated by treatment with THC and both JWH compounds. Collectively, these results demonstrate the potential for CB2 targeted therapeutics for treatment of inflammatory conditions involving aberrant pDC activity.

Immune Responses Regulated by Cannabidiol

“…There are two recent studies focused on CpG stimulation of IFN-a production from human plasmacytoid dendritic cells. 133,134 While these studies are focused primarily on THC and other CB 2 agonists, CBD was also used (1-10 lM) and did not affect IFN-a production. 133,134 It was interesting, however, that CBD suppressed the CD83 dendritic cell activation marker on dendritic cells derived from HIV + , but not healthy, individuals.…”

“…133,134 While these studies are focused primarily on THC and other CB 2 agonists, CBD was also used (1-10 lM) and did not affect IFN-a production. 133,134 It was interesting, however, that CBD suppressed the CD83 dendritic cell activation marker on dendritic cells derived from HIV + , but not healthy, individuals. 134 Reduction in dendritic cell CD83 signaling can compromise T cell function, 135 although additional studies using CBD in human dendritic cells and T cells are needed to establish the consequences of CBDinduced reduction in CD83 on HIV + dendritic cells.…”

Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB2 receptor in the arthritis progression and pain: an updated review

“…Using molecular docking and molecular dynamics analyses, Fechtner et al showed that JWH-015 favourably bound to glucocorticoid receptor (GR), and GR knockdown reduced the anti-inflammatory effect of JWH-015 [ 129 ]. JWH-015 and JWH-133 modulate interferon α (IFNα) and TNFα responses in primary human plasmacytoid dendritic cells [ 130 ]. In an in vitro study of IL-1β-stimulated synoviocytes, JWH-133 mediated the association of CB 2 with TAK1 kinase to increase nuclear translocation of the transcription factors NF-κB p65 and AP-1 [ 110 ].…”

The Role of Cannabinoids in Allergic Diseases: Collegium Internationale Allergologicum (CIA) Update 2020

“…In human monocytederived dendritic cells (DCs), the expression of all the components of the ECS has been described [64] and several inflammatory models showed the capacity of cannabinoids to modulate DC function. AEA and THC inhibit pro-inflammatory cytokine production and the capacity of DCs to polarize Th1 and Th17 responses [65][66][67]. THC induces apoptosis in murine DCs, providing a potential immunosuppression mechanism of immune cells [68].…”

“…Metabolic reprogramming can govern the function of T cells, macrophages, and DCs. Immune activation is mainly linked to a glycolysis-driven upregulation of anabolic processes, [184,185] AEA, 2-AG, THC, and CBD inhibit cytokine production [61,81,186,187] AEA and PEA stimulate phagocytosis [188,189] 2-AG, THC, and WIN55212-2 modulate ROS production [187,190] CBD induces apoptosis [191] Dendritic cells (DCs) CB1 and CB2 [43,64] AEA, THC, JWH-015, and JWH-133 inhibit inflammatory cytokine production [65,66] AEA and THC inhibit the capacity to induce Th1 and Th17 responses [65,67] THC induces apoptosis [68] THC impairs human monocyte-derived DC differentiation [192] Neutrophils CB1 and CB2 [70,193] AEA, CBD, and CB2 signalling reduce cell migration [69,70] AEA and 2-AG induce cell activation and the release of antimicrobial effectors [70,71,194] NK cells CB1 and CB2 [60] 2-AG and THC inhibit cytolytic activity [72,74] CB2 signalling reduces cell migration [74] O-1602 induces high cytolytic activity and cytokine production [49] Eosinophils CB1 and CB2 [195] 2-AG increases cell recruitment [195,196] WIN55212-2 reduces cell recruitment [197] Mast cells CB1 and CB2 [73,103,198] AEA and AEA-derived compounds inhibit cell maturation and degranulation…”