Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties.
Cannabinoid receptor activation by agents such as Δ(9)-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.
Department of Pathology, Microbiology and Immunology, University of South Carolina, School of Medicine, Columbia, SC, USA.
Venkatesh L
VL
Hegde
Mitzi
M
Nagarkatti
Prakash S
PS
Nagarkatti
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D001853:Bone Marrow / Q000473:pathology; D039481:CD11b Antigen / Q000096:biosynthesis; D001892:Camphanes / Q000494:pharmacology; D002478:Cells, Cultured; D013759:Dronabinol / Q000008:administration & dosage*; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019650:Hematopoietic Stem Cell Mobilization; D007165:Immunosuppression Therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000276:immunology / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000276:immunology / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000096:biosynthesis; D000077285:Rimonabant
D019138:Antibodies, Blocking; D039481:CD11b Antigen; D001892:Camphanes; C503133:Gr-1 protein, mouse; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D019707:Receptors, Chemokine; C110630:SR 144528; D016179:Granulocyte Colony-Stimulating Factor; D013759:Dronabinol; D000077285:Rimonabant