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Rac signal adaptation controls neutrophil mobilization from the bone marrow
- Source :
- Science Signaling, Vol. 9, No 459 (2016) P. ra124, Science Signaling, 9(459):ra124. American Association for the Advancement of Science
- Publication Year :
- 2016
- Publisher :
- American Association for the Advancement of Science, 2016.
-
Abstract
- Mobilization of neutrophils from the bone marrow determines neutrophil blood counts and thus is medically important. Balanced neutrophil mobilization from the bone marrow depends on the retention-promoting chemokine CXCL12 and its receptor CXCR4 and the egression-promoting chemokine CXCL2 and its receptor CXCR2. Both pathways activate the small guanosine triphosphatase Rac, leaving the role of this signaling event in neutrophil retention and egression ambiguous. On the assumption that active Rac determines persistent directional cell migration, we generated a mathematical model to link chemokine-mediated Rac modulation to neutrophil egression time. Our computer simulation indicated that, in the bone marrow, where the retention signal predominated, egression time strictly depended on the time it took Rac to return to its basal activity (namely, adaptation). This prediction was validated in mice lacking the Rac inhibitor ArhGAP15. Neutrophils in these mice showed prolonged Rac adaptation and cell-autonomous retention in the bone marrow. Our model thus demonstrates that mobilization in the presence of two spatially defined opposing chemotactic cues strictly depends on inhibitors shaping the time course of signal adaptation. Furthermore, our findings might help to find new modes of intervention to treat conditions characterized by excessively low or high circulating neutrophils.
- Subjects :
- 0301 basic medicine
Chemokine
Receptors, CXCR4
Neutrophils
Knockout
CXCR4
Biochemistry
03 medical and health sciences
Mice
0302 clinical medicine
Bone Marrow
Receptors
medicine
Animals
CXC chemokine receptors
Receptor
Molecular Biology
Mice, Knockout
biology
Signal Transduction/physiology
GTPase-Activating Proteins
Cell migration
Chemotaxis
Cell Biology
CXCR4/genetics/metabolism
Chemokine CXCL12
Cell biology
rac GTP-Binding Proteins
CXCL2
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
GTPase-Activating Proteins/genetics/metabolism
Immunology
Bone Marrow/enzymology
biology.protein
Neutrophils/enzymology
Bone marrow
Rac GTP-Binding Proteins/genetics/metabolism
Chemokine CXCL12/genetics/metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 19379145 and 19450877
- Database :
- OpenAIRE
- Journal :
- Science Signaling, Vol. 9, No 459 (2016) P. ra124, Science Signaling, 9(459):ra124. American Association for the Advancement of Science
- Accession number :
- edsair.doi.dedup.....34578d9dc194677a1f9bb626e66ac41e