title: Rac signal adaptation controls neutrophil mobilization from the bone marrow.
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.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Carlo Cosimo
authors.initials: CC
authors.lastname: Campa
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Germena
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ciraolo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Copperi
authors.affiliation: Department of Mathematical Sciences, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sapienza
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Franco
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ghigo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Camporeale
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Augusta
authors.initials: A
authors.lastname: Di Savino
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Martini
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Pettenkoferstrasse 9, 80336 Munich, Germany.|Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, Netherlands.
authors.forename: Remco T A
authors.initials: RT
authors.lastname: Megens
authors.affiliation: Biomedical Center, Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, 82152 Planegg-Martinsried, Germany.
authors.forename: Angela R M
authors.initials: AR
authors.lastname: Kurz
authors.affiliation: Biomedical Center, Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, 82152 Planegg-Martinsried, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheiermann
authors.affiliation: Biomedical Center, Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, 82152 Planegg-Martinsried, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
authors.affiliation: Department of Applied Science and Technology, Institute of Condensed Matter Physics and Complex Systems, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy. emilio.hirsch@unito.it andrea.gamba@polito.it.|Human Genetics Foundation, Via Nizza 52, 10126 Torino, Italy.|Istituto Nazionale di Fisica Nucleare, Via Giuria 1, 10125 Torino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gamba
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy. emilio.hirsch@unito.it andrea.gamba@polito.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000201:enzymology*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D020690:GTPase-Activating Proteins; D019718:Receptors, CXCR4; D020744:rac GTP-Binding Proteins