P-selectin glycoprotein ligand-1 deficiency augments G-CSF induced myeloid cell mobilization

Abstract

The effect of granulocyte colony-stimulating factor (G-CSF) was investigated in P-selectin glycoprotein ligand-1 (PSGL-1) deficient (PSGL-1(-/-)) and wild-type (PSGL-1(+/+)) mice to establish the role of this mucin in myeloid cell mobilization. G-CSF activates tissue proteases that cleave adhesion molecules, thus enhances the mobilization of myeloid cells and haematopoietic stem cells. Cytopenia was induced with a single dose of cyclophosphamide. In PSGL-1(-/-) animals, we observed a delayed extravasation of mature myeloid cells from the peripheral vessels into the tissue compartments and their faster mobilization from the bone marrow. Subsequently, animals received G-CSF twice a day for 4 days. Neutrophil and monocyte counts increased upon completion of G-CSF treatment and both values were significantly higher in PSGL-1(-/-) mice; 47.7 versus 28.3 G/l for neutrophils and 4.1 versus 2.0 G/l for monocytes. The ratio of atypical myeloid cells was also elevated. Analyzing the causes of the above differences, we identified a 4-fold increase in the colony-forming unit (CFU-GM) counts of the peripheral blood in PSGL-1(-/-) mice, compared to wild-type animals. A significantly elevated number of CFU-GM was detected also in the femurs of PSGL-1(-/-) mice, 4 and 5 days after cyclophosphamide treatment and these values paralleled with the elevation of CD34+/CD117+ stem cell counts in the peripheral blood. Our data suggest, that in the absence of PSGL-1, G-CSF was more potent in elevating absolute myeloid cell numbers by acting on cell release from the bone marrow, maturation from circulating precursor cells in the peripheral blood and prolonged retainment in the circulation.

PSGL-1 Immune Checkpoint Inhibition for CD4+ T Cell Cancer Immunotherapy

“…In addition to facilitating cell homing, PSGL-1 can affect the frequency of circulating myeloid cells. An induced cytopenia model comparing WT and Selplg −/− mice demonstrated that PSGL-1 constricts release of myeloid precursors from the bone marrow, as well as promoting extravasation of neutrophils and monocytes from blood vessels ( 146 ). A wide variety of research has revealed the numerous roles that PSGL-1 plays in adhesion, migration, and in directing the immune response to inflammation.…”

The Interaction of Selectins and PSGL-1 as a Key Component in Thrombus Formation and Cancer Progression

“…In multiple myeloma, PSGL-1 is highly expressed on the myeloma cells and regulates their homing into bone marrow microenvironment [ 141 ]. However, the mobilization of mature myeloid cells and their precursors from the bone marrow is also mediated by PSGL-1 via the interaction of leukocytes with endothelial or stromal cells [ 142 ]. Finally, function of PSGL-1 is associated with hematogenous metastasis of lymphomas as the downregulation of its expression in metastatic lymphoid cells resulted in a significant reduction of liver and spleen colonization in a dose-dependent manner [ 143 ].…”

RUNX1/ETO blocks selectin-mediated adhesion via epigenetic silencing of PSGL-1

“…This is suggested by studies with PSGL-1-deficient BCR/ABL cells, which are impaired in engraftment potential in a mouse transplantation model. 49 PSGL-1 deficiency also augments the mobilization of hematopoietic progenitor cells into the peripheral blood, 50 thereby suggesting that RE-mediated PSGL-1 repression reduces cell adhesion in t(8;21)+ hematopoietic progenitor cells in the bone marrow. This may partially explain the favorable response of core-binding factor leukemias toward chemotherapy treatment.…”