title: Characterization of endocannabinoid-mediated induction of myeloid-derived suppressor cells involving mast cells and MCP-1.
abstract: Endocannabinoids are lipid-signaling molecules found in the nervous system; however, their precise role in the periphery is unclear. In the current study, we observed that a single i.p. administration of AEA caused rapid induction of MDSCs. The MDSCs contained a mixture of granulocytic and monocytic subtypes and expressed Arg-1 and iNOS. The MDSCs suppressed T cell proliferation in vitro and used iNOS to mediate their effect. Moreover, adoptive transfer of MDSCs led to suppression of mBSA-induced DTH. Through the use of pharmacological inhibition, as well as genetic knockout mice, we found that the induction of MDSCs by AEA was CB1-dependent. The induction of MDSCs by AEA was reduced significantly in mast cell-deficient mice, while maintained in LPS-insensitive mice, showing that the induction of MDSCs by AEA was dependent, at least in part, on mast cells and independent of TLR4. Chemokine analysis of AEA- treated WT mice showed an early spike of MCP-1, which was decreased in Kit(W/W-sh) mice, showing a role of mast cells in the secretion of MCP-1 in response to AEA. Also, use of antibodies against MCP-1 or mice deficient in MCP-1 confirmed the role played by MCP-1. Interestingly, MCP-1 played a significant role in the induction of monocytic but not granulocytic MDSCs. Our studies demonstrate for the first time that endocannaboinids activate CB1 on mast cells to induce MCP-1, which facilitates recruitment of monocytic MDSCs.
authors: 1.Microbiology and Immunology, University of South Carolina School of Medicine, 6439 Garner's Ferry Rd., Columbia, SC 29208, USA. mnagark@uscmed.sc.edu.
authors: Austin R
authors: AR
authors: Jackson
authors: Venkatesh L
authors: VL
authors: Hegde
authors: Prakash S
authors: PS
authors: Nagarkatti
authors: Mitzi
authors: M
authors: Nagarkatti
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D039481:CD11b Antigen / Q000032:analysis; D018932:Chemokine CCL2 / Q000502:physiology*; D063388:Endocannabinoids / Q000494:pharmacology*; D005260:Female; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects* / Q000502:physiology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000502:physiology; D019707:Receptors, Chemokine / Q000032:analysis
chemical_list: D001095:Arachidonic Acids; D039481:CD11b Antigen; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D063388:Endocannabinoids; C503133:Gr-1 protein, mouse; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D019707:Receptors, Chemokine; C078814:anandamide
keywords: CB1; anandamide; chemokine; monocytic MDSCs