TY - JOUR
T1 - Characterization of endocannabinoid-mediated induction of myeloid-derived suppressor cells involving mast cells and MCP-1
AU - Jackson, Austin R.
AU - Hegde, Venkatesh L.
AU - Nagarkatti, Prakash S.
AU - Nagarkatti, Mitzi
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2014/4
Y1 - 2014/4
N2 - 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 KitW/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.
AB - 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 KitW/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.
KW - Anandamide
KW - CB1
KW - Chemokine
KW - Monocytic MDSCs
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U2 - 10.1189/jlb.0613350
DO - 10.1189/jlb.0613350
M3 - Article
C2 - 24319288
AN - SCOPUS:84899811334
VL - 95
SP - 609
EP - 619
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
SN - 0741-5400
IS - 4
ER -