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GRK6 deficiency is associated with enhanced CXCR4‐mediated neutrophil chemotaxis in vitro and impaired responsiveness to G‐CSF in vivo
Author(s) -
Vroon Anne,
Heijnen Cobi J.,
Raatgever Roel,
Touw Ivo P.,
Ploemacher Rob E.,
Premont Richard T.,
Kavelaars Annemieke
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0703320
Subject(s) - biology , chemotaxis , receptor , bone marrow , cxcr4 , g protein coupled receptor kinase , medicine , granulocyte , haematopoiesis , endocrinology , chemokine , signal transduction , immunology , inflammation , microbiology and biotechnology , g protein coupled receptor , stem cell , biochemistry
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.