GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo

Jan 6, 2004Journal of leukocyte biology

Lack of GRK6 protein increases neutrophil movement toward CXCR4 signals in the lab but reduces their response to G-CSF in living organisms

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Abstract

Neutrophil mobilization in response to granulocyte-colony stimulating factor (G-CSF) is significantly impaired in GRK6-deficient mice.

SDF-1-induced movement of bone marrow-derived neutrophils is enhanced in GRK6-deficient mice.
Desensitization of the calcium response to SDF-1 is impaired in neutrophils lacking GRK6.
In GRK6-deficient mice, the increase in circulating neutrophils following pegylated-G-CSF injection is significantly lower compared to wild-type mice.
Early neutrophil mobilization in response to G-CSF is also impaired in GRK6-deficient mice.
Neutrophil production remains normal in GRK6-deficient and wild-type mice as indicated by similar bone marrow neutrophil percentages after G-CSF treatment.
GRK6-deficient neutrophils retain increased sensitivity to SDF-1 chemotaxis even after G-CSF treatment.

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The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) signaling pathway is thought to play an important role in the induction of neutrophil mobilization from the bone marrow in response to granulocyte-colony stimulating factor (G-CSF) treatment. CXCR4 belongs to the family of G protein-coupled receptors. Multiple members of this receptor family are desensitized by agonist-induced G protein-coupled receptor kinase (GRK)-mediated phosphorylation. Here, we demonstrate that in vitro SDF-1-induced chemotaxis of bone marrow-derived neutrophils from GRK6-deficient mice is significantly enhanced and that desensitization of the calcium response to SDF-1 is impaired in GRK6-/- neutrophils. CXCR4 activation by SDF-1 provides a key retention signal for hematopoietic cells in the bone marrow. It is interesting that we observed that in the absence of GRK6, the G-CSF-induced increase in circulating neutrophils is profoundly impaired. Three days after injection of pegylated-G-CSF, significantly lower numbers of circulating neutrophils were observed in GRK6-/- as compared with wild-type (WT) mice. In addition, early/acute neutrophil mobilization in response to G-CSF (3 h after treatment) was also impaired in GRK6-/- mice. However, blood neutrophil levels in untreated GRK6-/- and WT mice were not different. Moreover, the percentage of neutrophils in the bone marrow after G-CSF treatment was increased to the same extent in WT and GRK6-/- mice, indicating that neutrophil production is normal in the absence of GRK6. However, the increased chemotactic sensitivity of GRK6-/- neutrophils to SDF-1 was retained after G-CSF treatment. In view of these data, we suggest that the impaired G-CSF-induced neutrophil mobilization in the absence of GRK6 may be a result of enhanced CXCR4-mediated retention of PMN in the bone marrow.

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GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo

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