Selective CB2 receptor activation ameliorates EAE by reducing Th17 differentiation and immune cell accumulation in the CNS |
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Authors: | Weimin Kong Hongbo Li Ronald F. Tuma Doina Ganea |
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Affiliation: | 1. Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, United States;2. Center for Substance Abuse Research and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, United States |
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Abstract: | CB2, the cannabinoid receptor expressed primarily on hematopoietic cells and activated microglia, mediates the immunoregulatory functions of cannabinoids. The involvement of CB2 in EAE has been demonstrated by using both endogenous and exogenous ligands. We showed previously that CB2 selective agonists inhibit leukocyte rolling and adhesion to CNS microvasculature and ameliorate clinical symptom in both chronic and remitting-relapsing EAE models. Here we showed that Gp1a, a highly selective CB2 agonist, with a four log higher affinity for CB2 than CB1, reduced clinical scores and facilitated recovery in EAE in conjunction with long term reduction in demyelination and axonal loss. We also established that Gp1a affected EAE through at least two different mechanisms, i.e. an early effect on Th1/Th17 differentiation in peripheral immune organs, and a later effect on the accumulation of pathogenic immune cells in the CNS, associated with reductions in the expression of CNS and T cell chemokine receptors, chemokines and adhesion molecules. This is the first report on the in vivo CB2-mediated Gp1a inhibition of Th17/Th1 differentiation. We also confirmed the Gp1a-induced inhibition of Th17/Th1 differentiation in vitro, both in non-polarizing and polarizing conditions. The CB2-induced inhibition of Th17 differentiation is highly relevant in view of recent studies emphasizing the importance of pathogenic self-reactive Th17 cells in EAE/MS. In addition, the combined effect on Th17 differentiation and immune cell accumulation into the CNS, emphasize the relevance of CB2 selective ligands as potential therapeutic agents in neuroinflammation. |
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Keywords: | APC, antigen-presenting cell BBB, blood brain barrier CB1, cannabinoid receptor 1 CB2, cannabinoid receptor 2 CNS, central nervous system DC, dendritic cell EAE, experimental autoimmune encephalomyelitis FACS, fluorescence activated cell sorter LPS, lipopolysaccharide MNCs, mononuclear cells MOG, myelin oligodendrocyte glycoprotein MS, multiple sclerosis PBS, phosphate buffered saline PT, pertussis toxin qRT-PCR, quantitative RT-PCR TCR, T cell receptor |
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