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.
Highlights
Cannabinoids are compounds derived from the Cannabis sativa plant and exert many effects on the immune system [1,2,3]
We stained the lymph node cells for intracellular IL-17 by flow cytometry and calculated the absolute numbers of Th17 cells. mBSA immunization caused significant increase in IL-17 producing cells when compared to naıve mice, and AEA treatment significantly reduced the number of IL-17 producing cells [Fig 1C]
Our current study shows that when endogenous cannabinoids are given as a treatment they can attenuate Th17 cell-mediated inflammation and the subsequent mBSA-induced hypersensitivity
Summary
Cannabinoids are compounds derived from the Cannabis sativa plant and exert many effects on the immune system [1,2,3]. The major members of this family of compounds include Arachidonyl Ethanolamide [AEA, Anandamide] and 2-Arachidonyl Glycerol [2-AG]. These compounds act by activating specific receptors called cannabinoid receptors, of which there are two, CB1 and CB2. Changes in the endocannabinoid system have been reported in liver injury [7], colitis [8], and diabetes [9]. When both cannabinoid receptors were knocked out, mice were more prone to developing allergic hypersensitivity [10]. This report suggested a role of the endogenous cannabinoid system in regulation of allergic inflammation
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