title: Selective CB2 receptor activation ameliorates EAE by reducing Th17 differentiation and immune cell accumulation in the CNS.
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.
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, United States.
authors.forename: Weimin
authors.initials: W
authors.lastname: Kong
authors.affiliation: Center for Substance Abuse Research and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, United States.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Li
authors.affiliation: Center for Substance Abuse Research and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, United States.
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Tuma
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, United States. Electronic address: dganea@temple.edu.
authors.forename: Doina
authors.initials: D
authors.lastname: Ganea
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology*; D018925:Chemokines / Q000378:metabolism; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007192:Indenes / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D015213:Neuroimmunomodulation; D010446:Peptide Fragments / Q000276:immunology; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D007192:Indenes; D063308:Myelin-Oligodendrocyte Glycoprotein; C553580:N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-1,4-dihydro-6-methylindeno(1,2-c)pyrazole-3-carboxamide; D010446:Peptide Fragments; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D019707:Receptors, Chemokine; C517781:myelin oligodendrocyte glycoprotein (34-56)
keywords: APC; BBB; CB1; CB2; CNS; Cannabinoid receptor; Chemokines; DC; EAE; FACS; Gp1a; LPS; MNCs; MOG; MS; PBS; PT; T cell receptor; TCR; Th17 differentiation; antigen-presenting cell; blood brain barrier; cannabinoid receptor 1; cannabinoid receptor 2; central nervous system; dendritic cell; experimental autoimmune encephalomyelitis; fluorescence activated cell sorter; lipopolysaccharide; mononuclear cells; multiple sclerosis; myelin oligodendrocyte glycoprotein; pertussis toxin; phosphate buffered saline; qRT-PCR; quantitative RT-PCR