TY - JOUR
T1 - Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties
AU - Hegde, Venkatesh L.
AU - Nagarkatti, Mitzi
AU - Nagarkatti, Prakash S.
PY - 2010/12
Y1 - 2010/12
N2 - Cannabinoid receptor activation by agents such as δ9-tetrahydrocannabinol (THC) is known to trigger immune suppression. Here, we show that administration of THC in mice leads to rapid and massive expansion of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) expressing functional arginase and exhibiting potent immunosuppressive properties both in vitro and in vivo. The induction of MDSC by THC was associated with a significant increase in granulocyte CSF. Moreover, administration of anti-granulocyte CSF Ab inhibited the induction of MDSC by THC. THC was able to induce MDSC in TLR4 mutant C3H and C57BL10/ScN mice and hence acted independently of TLR4. Accumulation of MDSC in the periphery with a corresponding decrease in the proportion of CD11b+Gr-1+ cells in the bone marrow, as well as in vivo BrdU labeling and cell-cycle analysis, showed that THC induced mobilization of these cells from bone marrow and their expansion in the periphery. Use of selective antagonists SR141716A and SR144528 against cannabinoid receptors 1 and 2, respectively, as well as receptor-deficient mice showed that induction of MDSC was mediated through activation of both cannabinoid receptors 1 and 2. These studies demonstrate that cannabinoid receptor signaling may play a crucial role in immune regulation via the induction of MDSC.
AB - Cannabinoid receptor activation by agents such as δ9-tetrahydrocannabinol (THC) is known to trigger immune suppression. Here, we show that administration of THC in mice leads to rapid and massive expansion of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) expressing functional arginase and exhibiting potent immunosuppressive properties both in vitro and in vivo. The induction of MDSC by THC was associated with a significant increase in granulocyte CSF. Moreover, administration of anti-granulocyte CSF Ab inhibited the induction of MDSC by THC. THC was able to induce MDSC in TLR4 mutant C3H and C57BL10/ScN mice and hence acted independently of TLR4. Accumulation of MDSC in the periphery with a corresponding decrease in the proportion of CD11b+Gr-1+ cells in the bone marrow, as well as in vivo BrdU labeling and cell-cycle analysis, showed that THC induced mobilization of these cells from bone marrow and their expansion in the periphery. Use of selective antagonists SR141716A and SR144528 against cannabinoid receptors 1 and 2, respectively, as well as receptor-deficient mice showed that induction of MDSC was mediated through activation of both cannabinoid receptors 1 and 2. These studies demonstrate that cannabinoid receptor signaling may play a crucial role in immune regulation via the induction of MDSC.
KW - Arginase
KW - Cannabinoid receptors
KW - Granulocyte CSF
KW - Immune suppression
KW - Myeloid-derived suppressor cells
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U2 - 10.1002/eji.201040667
DO - 10.1002/eji.201040667
M3 - Article
C2 - 21110319
AN - SCOPUS:78649605467
SN - 0014-2980
VL - 40
SP - 3358
EP - 3371
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 12
ER -