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GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo.
J Leukoc Biol. 2004 Apr; 75(4):698-704.JL

Abstract

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.

Authors+Show Affiliations

Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

14704365

Citation

Vroon, Anne, et al. "GRK6 Deficiency Is Associated With Enhanced CXCR4-mediated Neutrophil Chemotaxis in Vitro and Impaired Responsiveness to G-CSF in Vivo." Journal of Leukocyte Biology, vol. 75, no. 4, 2004, pp. 698-704.
Vroon A, Heijnen CJ, Raatgever R, et al. GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo. J Leukoc Biol. 2004;75(4):698-704.
Vroon, A., Heijnen, C. J., Raatgever, R., Touw, I. P., Ploemacher, R. E., Premont, R. T., & Kavelaars, A. (2004). GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo. Journal of Leukocyte Biology, 75(4), 698-704.
Vroon A, et al. GRK6 Deficiency Is Associated With Enhanced CXCR4-mediated Neutrophil Chemotaxis in Vitro and Impaired Responsiveness to G-CSF in Vivo. J Leukoc Biol. 2004;75(4):698-704. PubMed PMID: 14704365.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo. AU - Vroon,Anne, AU - Heijnen,Cobi J, AU - Raatgever,Roel, AU - Touw,Ivo P, AU - Ploemacher,Rob E, AU - Premont,Richard T, AU - Kavelaars,Annemieke, Y1 - 2004/01/02/ PY - 2004/1/6/pubmed PY - 2004/5/7/medline PY - 2004/1/6/entrez SP - 698 EP - 704 JF - Journal of leukocyte biology JO - J Leukoc Biol VL - 75 IS - 4 N2 - 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. SN - 0741-5400 UR - https://www.unboundmedicine.com/medline/citation/14704365/GRK6_deficiency_is_associated_with_enhanced_CXCR4_mediated_neutrophil_chemotaxis_in_vitro_and_impaired_responsiveness_to_G_CSF_in_vivo_ L2 - https://doi.org/10.1189/jlb.0703320 DB - PRIME DP - Unbound Medicine ER -