G-CSF mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

Anja Köhler, Katia De Filippo, Mike Hasenberg, Cindy van den Brandt, Emma Nye, Martin P. Hosking, Thomas E. Lane, Linda Männ, Richard M. Ransohoff, Anja E. Hauser, Oliver Winter, Burkhart Schraven, Hartmut Geiger, Nancy Hogg and Matthias Gunzer


Emergency mobilization of neutrophil granulocytes (neutrophils) from the bone marrow (BM) is a key event of early cellular immunity. The hematopoietic cytokine Granulocyte-Colony-Stimulating-Factor (G-CSF) stimulates this process, but it is unknown how individual neutrophils respond in situ. We show by intravital 2-photon microscopy that a systemic dose of human clinical-grade G-CSF rapidly induces motility and entry of neutrophils into blood vessels within the tibial BM of mice. Simultaneously the neutrophil attracting chemokine KC (Cxcl1) spikes in the blood. In mice lacking the KC receptor, Cxcr2, G-CSF fails to mobilize neutrophils and also antibody blockade of Cxcr2 inhibits mobilization and induction of neutrophil motility in the BM. KC is expressed by megakaryocytes and endothelial cells in situ and released in vitro by megakaryocytes isolated directly from BM. This production of KC is strongly increased by thrombopoietin. Importantly, systemic G-CSF rapidly induces the increased production of thrombopoietin in BM. Accordingly, a single injection of thrombopoietin mobilizes neutrophils with similar kinetics as G-CSF and mice lacking the thrombopoietin receptor show impaired neutrophil mobilization after short-term G CSF administration. Thus, a network of signaling molecules, chemokines and cells controls neutrophil release from the BM. Their mobilization involves rapidly induced Cxcr2-mediated motility controlled by thrombopoietin as pacemaker.

  • Submitted September 20, 2010.
  • Accepted December 20, 2010.