Research ArticleImmunology

Rac signal adaptation controls neutrophil mobilization from the bone marrow

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Sci. Signal.  20 Dec 2016:
Vol. 9, Issue 459, pp. ra124
DOI: 10.1126/scisignal.aah5882

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A balance between staying and leaving

Neutrophils generated in the bone marrow are critical for inflammatory responses that fight infection. However, too many or too few neutrophils in the bloodstream are detrimental. The number of circulating neutrophils is determined by the balance between signaling mediated by the chemokines CXCL12, which retains neutrophils in the bone marrow, and CXCL2, which recruits neutrophils to tissues. Both CXCL12 and CXCL2 activate the small GTPase Rac. Campa et al. performed mathematical modeling and showed that the time it took active Rac to return to baseline determined how long neutrophils were retained in the bone marrow. Mice that were genetically deficient for a Rac inhibitor retained more neutrophils in the bone marrow and had fewer neutrophils in the blood than wild-type mice. Thus, these findings might highlight new opportunities to treat neutrophilia (too many circulating neutrophils) or neutropenia (too few circulating neutrophils).

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.

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