title: Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol.
abstract: BACKGROUND
  Myeloid-derived suppressor cells (MDSCs) are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis.
  
  
  RESULTS
  Polyclonal activation of T cells, following injection of concanavalin A (ConA), in C57BL/6 mice caused acute hepatitis, characterized by significant increase in aspartate transaminase (AST), induction of inflammatory cytokines, and infiltration of mononuclear cells in the liver, leading to severe liver injury. Administration of cannabidiol (CBD), a natural non-psychoactive cannabinoid, after ConA challenge, inhibited hepatitis in a dose-dependent manner, along with all of the associated inflammation markers. Phenotypic analysis of liver infiltrating cells showed that CBD-mediated suppression of hepatitis was associated with increased induction of arginase-expressing CD11b(+)Gr-1(+) MDSCs. Purified CBD-induced MDSCs could effectively suppress T cell proliferation in vitro in arginase-dependent manner. Furthermore, adoptive transfer of purified MDSCs into naïve mice conferred significant protection from ConA-induced hepatitis. CBD failed to induce MDSCs and suppress hepatitis in the livers of vanilloid receptor-deficient mice (TRPV1(-/-)) thereby suggesting that CBD primarily acted via this receptor to induce MDSCs and suppress hepatitis. While MDSCs induced by CBD in liver consisted of granulocytic and monocytic subsets at a ratio of ∼2∶1, the monocytic MDSCs were more immunosuppressive compared to granulocytic MDSCs. The ability of CBD to induce MDSCs and suppress hepatitis was also demonstrable in Staphylococcal enterotoxin B-induced liver injury.
  
  
  CONCLUSIONS
  This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents such as CBD, which trigger MDSCs through activation of TRPV1 vanilloid receptors may constitute a novel therapeutic modality to treat inflammatory diseases.
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
authors.forename: Venkatesh L
authors.initials: VL
authors.lastname: Hegde
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002185:Cannabidiol / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D003208:Concanavalin A / Q000009:adverse effects; D016207:Cytokines / Q000037:antagonists & inhibitors; D055808:Drug Discovery; D004768:Enterotoxins / Q000633:toxicity; D005260:Female; D019693:Hepatitis, Autoimmune / Q000188:drug therapy / Q000209:etiology / Q000276:immunology* / Q000378:metabolism*; D007108:Immune Tolerance / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology*; D019707:Receptors, Chemokine / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D004768:Enterotoxins; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D003208:Concanavalin A; D002185:Cannabidiol; C031818:enterotoxin B, staphylococcal