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

Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.
Blood (Impact Factor: 10.45). 04/2011; 117(16):4349-57. DOI: 10.1182/blood-2010-09-308387
Source: PubMed


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 the 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 antibody blockade of Cxcr2 inhibits the mobilization and induction of neutrophil motility in the BM. KC is expressed by megakaryocytes and endothelial cells in situ and is released in vitro by megakaryocytes isolated directly from BM. This production of KC is strongly increased by thrombopoietin (TPO). Systemic G-CSF rapidly induces the increased production of TPO in BM. Accordingly, a single injection of TPO mobilizes neutrophils with kinetics similar to G-CSF, and mice lacking the TPO 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, and their mobilization involves rapidly induced Cxcr2-mediated motility controlled by TPO as a pacemaker.

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    • "In agreement with this, G-CSF-deficient mice have very few neutrophils in their blood and bone marrow (Semerad et al., 2002). Further, many circulatory inflammatory agents are involved in neutrophil mobilization during inflammation (leukotriene B4, CXCR2 ligands, C5a) in experimental animal models (Kohler et al., 2011). Thus, a single G-CSF injection results in rapid neutrophilia and neutropenic patients can be treated with G-CSF, CXCR2 ligands, or CXCR4 inhibitors to increase their numbers of circulating neutrophils (McDermott et al., 2011; Dale et al., 2011). "
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    ABSTRACT: Lack of sleep greatly affects our immune system. The present study investigates the acute effects of total sleep deprivation on blood neutrophils, the most abundant immune cell in our circulation and the first cell type recruited to sites of infection. Thus, the population diversity and function of circulating neutrophils were compared in healthy young men following one night of total sleep deprivation (TSD) or after 8 h regular sleep. We found that neutrophil counts were elevated after nocturnal wakefulness (2.0±0.2×109/l vs. 2.6±0.2×109/l, sleep vs. TSD, respectively) and the population contained more immature CD16dim/CD62Lbright cells (0.11±0.040×109/l [5.5±1.1%] vs. 0.26±0.020×109/l [9.9±1.4%]). As the rise in numbers of circulating mature CD16bright/CD62Lbright neutrophils was less pronounced, the fraction of this subpopulation showed a significant decrease (1.8±0.15×109/l [88±1.8%] vs. 2.1±0.12×109/l [82±2.8%]). The surface expression of receptors regulating mobilization of neutrophils from bone marrow was decreased (CXCR4 and CD49d on immature neutrophils; CXCR2 on mature neutrophils). The receptor CXCR2 is also involved in the production of reactive oxygen species (ROS), and in line with this, total neutrophils produced less ROS. In addition, following sleep loss, circulating neutrophils exhibited enhanced surface levels of CD11b, which indicates enhanced granular fusion and concomitant protein translocation to the membrane. Our findings demonstrate that sleep loss exerts significant effects on population diversity and function of circulating neutrophils in healthy men. To which extent these changes could explain as to why people with poor sleep patterns are more susceptible to infections warrants further investigation.
    Brain Behavior and Immunity 06/2014; 41(1). DOI:10.1016/j.bbi.2014.05.010 · 5.89 Impact Factor
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    • "Neutrophils are essential for early immune responses against microbial pathogens (K€ ohler et al, 2011). Thereby they feature two well-known main mechanisms of defence: phagocytosis (Behnsen et al, 2007) and intra-as well as extra-cellular destruction by chemical means (Segal, 2005; Nauseef, 2007; Winterbourn & Kettle, 2013). "
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    ABSTRACT: For a long time neutrophil granulocytes were considered simply as terminally differentiated cells with a limited life span and pathogen killing by phagocytosis and chemical toxicity being the sole mode of action. However, work during the last 10 years has started to change this view fundamentally. Modern understanding is that neutrophils have an enormous complexity of functions. This review discusses very recent findings on how neutrophils can control the spread of pathogens and mediate their killing by mechanisms such as formation of DNA nets, how they influence tumour growth and adaptive immune responses and how they manoeuvre inside the diverse compartments of the body. It will also describe how the normally protective functions of neutrophils can have deleterious consequences if they occur in an uncontrolled fashion. These exciting novel findings are likely to completely and permanently change our view of this central leucocyte population.
    British Journal of Haematology 10/2013; 164(2). DOI:10.1111/bjh.12608 · 4.71 Impact Factor
    • "While the relevance of these chemokines under steady-state conditions is still unclear, KC, another ligand for the mouse CXCR2, and CCL2 were shown to play a critical role in the egress from BM into blood of leukocyte populations during activating conditions, i.e., G-CSF treatment or infection, respectively (Martin et al., 2003; Serbina and Pamer, 2006). Interestingly, this effect was associated with their enhanced expression in proximity to the vascular compartment, thus facilitating target leukocyte migration toward blood circulation (Köhler et al., 2011; Shi et al., 2011). "
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    ABSTRACT: Responsiveness of maturing natural killer (NK) cells to chemotactic molecules directly affect their retention and relocation in selected bone marrow (BM) microenvironment during development, as well as their localization at sites of immune response during inflammatory diseases. BM is the main site of NK cell generation, providing microenvironmental signals required to sustain cell proliferation and differentiation. Drastic changes of expression and function of several chemoattractant receptors can be observed during progression from precursor NK cells to immature and mature NK cells. Indeed, the gradual decrease of CXCR4 expression parallels the increased expression of CXCR3, CCR1, and CX3CR1 and S1P(5) (Sphingosine-1-phosphate receptor 5) on mature DX5(+) NK cells. The chemokine CXCL12 is produced constitutively in the BM and, acting via CXCR4, is critical for retaining immature and mature NK cell subsets in the BM. During steady-state, the maintenance of NK cells into BM parenchyma depends on the equilibrium of CXCR4 retention and S1P(5) mobilizing functions, as the gradient of S1P coming from the sinusoids facilitates mature NK cell egress into circulation via S1P(5), when CXCR4/CXCL12-mediated retention decreases. Chemoattractants are also key factors for the response to inflammatory or infection conditions that promote mobilization of effector NK cells from storage compartments (including BM) to sites of disease or for NK cell recruitment/response during pathological conditions that affect BM integrity, including hematopoietic malignancies. In this review, we summarize what is known about the requirement for NK cell localization and exit from BM and how chemokine-mediated functions may affect BM NK cell development and immune responses.
    Frontiers in Immunology 01/2013; 4:12. DOI:10.3389/fimmu.2013.00012
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