Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties

Eur J Immunol. 2010 Dec;40(12):3358-71. doi: 10.1002/eji.201040667.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Blocking / administration & dosage
  • Bone Marrow / pathology
  • CD11b Antigen / biosynthesis
  • Camphanes / pharmacology
  • Cells, Cultured
  • Dronabinol / administration & dosage*
  • Granulocyte Colony-Stimulating Factor / genetics
  • Granulocyte Colony-Stimulating Factor / immunology
  • Granulocyte Colony-Stimulating Factor / metabolism*
  • Hematopoietic Stem Cell Mobilization
  • Immunosuppression
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism*
  • Myeloid Cells / pathology
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / immunology
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptor, Cannabinoid, CB2 / immunology
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Receptors, Chemokine / biosynthesis
  • Rimonabant

Substances

  • Antibodies, Blocking
  • CD11b Antigen
  • Camphanes
  • Gr-1 protein, mouse
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Receptors, Chemokine
  • SR 144528
  • Granulocyte Colony-Stimulating Factor
  • Dronabinol
  • Rimonabant