Anandamide Attenuates Th-17 Cell-Mediated Delayed-Type Hypersensitivity Response by Triggering IL-10 Production and Consequent microRNA Induction

Abstract

Endogenous cannabinoids [endocannabinoids] are lipid signaling molecules that have been shown to modulate immune functions. However, their role in the regulation of Th17 cells has not been studied previously. In the current study, we used methylated Bovine Serum Albumin [mBSA]-induced delayed type hypersensitivity [DTH] response in C57BL/6 mice, mediated by Th17 cells, as a model to test the anti-inflammatory effects of endocannabinoids. Administration of anandamide [AEA], a member of the endocannabinoid family, into mice resulted in significant mitigation of mBSA-induced inflammation, including foot pad swelling, cell infiltration, and cell proliferation in the draining lymph nodes [LN]. AEA treatment significantly reduced IL-17 and IFN-γ production, as well as decreased RORγt expression while causing significant induction of IL-10 in the draining LNs. IL-10 was critical for the AEA-induced mitigation of DTH response inasmuch as neutralization of IL-10 reversed the effects of AEA. We next analyzed miRNA from the LN cells and found that 100 out of 609 miRNA species were differentially regulated in AEA-treated mice when compared to controls. Several of these miRNAs targeted proinflammatory mediators. Interestingly, many of these miRNA were also upregulated upon in vitro treatment of LN cells with IL-10. Together, the current study demonstrates that AEA may suppress Th-17 cell–mediated DTH response by inducing IL-10 which in turn triggers miRNA that target proinflammatory pathways.

Protective Action of Anandamide and Its COX-2 Metabolite against L-Homocysteine-Induced NLRP3 Inflammasome Activation and Injury in Podocytes

“…Further studies are needed to address whether such approaches are also protective in glomerular injury associated with hHcys. Our finding that exogenous AEA produces anti-inflammatory effects is consistent with several reports documenting beneficial effects of exogenous AEA in inflammatory disease models, such as liver damage (Hegde et al, 2008), LPS-induced pulmonary inflammation AEA and Metabolites and NLRP3 Inflammasomes in Podocytes (Berdyshev et al, 1998), periodontitis (Rettori et al, 2012), hypoxia-ischemia injury (Lara-Celador et al, 2012), delayedtype hypersensitivity (Jackson et al, 2014), and viral demyelinating disease (Hernangomez et al, 2012).…”

Decreased circulating anandamide levels in preeclampsia

“…Anandamide attenuates Th17-mediated inflammation through in vivo increasing IL-10 production, which induces different microRNAs targeting pro-inflammatory cytokines and leading to IL-17 and interferon-γ reduction. 47 Endocannabinoids also mediate cytokine shift from Th1 to Th2 cytokines by suppression of cell activation, inhibition of pro-inflammatory cytokine production and nuclear factor-κB-dependent apoptosis. 48 Both anandamide and exogen Δ 9 -THC increase regulatory T-cell functions through CB1 and CB2, resulting in significant suppression of inflammatory cytokines and chemokines.…”

MicroRNA let-7d is a target of cannabinoid CB 1 receptor and controls cannabinoid signaling

“…Some previous studies had focused on the effect of cannabinoid ligands on miRNA expression in cells of non-neural origin (Hegde et al, 2013;Sreevalsan and Safe, 2013;Jackson et al, 2014). In these studies let-7d was not among the miRNAs whose expression was reported to change upon cannabinoid challenge.…”