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Rac signal adaptation controls neutrophil mobilization from the bone marrow

Campa, Carlo Cosimo
Germena, Giulia
Ciraolo, Elisa
Copperi, Francesca
Sapienza, Anna
Franco, Irene
Ghigo, Alessandra
Camporeale, Annalisa
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Published in Science Signaling. 2016, vol. 9, no. 459, p. ra124
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.
Keywords AnimalsBone Marrow/enzymologyChemokine CXCL12/genetics/metabolismGTPase-Activating Proteins/genetics/metabolismMiceMiceKnockoutNeutrophils/enzymologyReceptorsCXCR4/genetics/metabolismSignal Transduction/physiologyRac GTP-Binding Proteins/genetics/metabolism
PMID: 27999173
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Research group Groupe Christoph Scheiermann (995)
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CAMPA, Carlo Cosimo et al. Rac signal adaptation controls neutrophil mobilization from the bone marrow. In: Science Signaling, 2016, vol. 9, n° 459, p. ra124. doi: 10.1126/scisignal.aah5882

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Deposited on : 2018-12-05

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