G-CSF Is an Essential Regulator of Neutrophil Trafficking from the Bone Marrow to the Blood

Abstract

Neutrophils are released from the bone marrow in a regulated fashion to maintain homeostatic levels in the blood and to respond to physiological stresses, including infection. We show that under basal conditions granulocyte colony-stimulating factor (G-CSF) is an essential regulator of neutrophil release from the bone marrow. Nonredundant signals generated by the membrane-proximal 87 amino acids of the G-CSF receptor (G-CSFR) are sufficient to mediate this response. Surprisingly, G-CSFR expression on neutrophils is neither necessary nor sufficient for their mobilization from the bone marrow, suggesting that G-CSF induces neutrophil mobilization indirectly through the generation of trans-acting signals. Evidence is provided suggesting that downregulation of stromal cell-derived factor 1 expression in the bone marrow may represent such a signal.

Cytokine receptors and hematopoietic differentiation

“…Treatment of the mice with G-CSF did not alter the number of myeloid or erythroid progenitors in bone marrow, supporting the stochastic/permissive model. Interestingly, aspects of neutrophil function, such as chemotaxis and G-CSF-stimulated mobilization of neutrophils and hematopoietic progenitors to peripheral blood, remained impaired (Semerad et al, 1999;Semerad et al, 2002). Overall, these experiments suggest that the signals generated by specific receptors are not required for lineage commitment, but rather that the receptors provide nonspecific survival and proliferation signals, and, in some instances, maturation signals.…”

“…This was demonstrated for the G-CSFRnull mouse. Mice with a null mutation of the G-CSFR, like G-CSF-null mice, had ineffective granulopoiesis with chronic neutropenia, a decrease in mature myeloid elements in their bone marrow and diminished neutrophil release from bone marrow Liu et al, 1996;Semerad et al, 2002). Surprisingly, however, the bone marrow of G-CSFR-deficient mice has only a modest reduction in the committed myeloid progenitors.…”

pDP4, a novel glycoprotein secreted by mature granulocytes, is regulated by transcription factor PU.1

“…They are produced in the bone marrow and are released into the peripheral blood as mature cells in a regulated fashion maintaining homeostatic levels of circulating neutrophils. 21 Release of neutrophils from the bone marrow is rapidly increased in response to inflammatory or infectious stimuli. Although the mechanisms are largely unknown, granulocytic mobilization from the bone marrow appears to be a highly regulated process.…”

Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

“…Accumulating evidence suggests that neutrophil egress from bone marrow is antagonistically regulated by CXC chemokine receptors CXCR2 and CXCR4, which are both expressed on neutrophils [Semerad et al, 2002;Eash et al, 2010;Wengner et al, 2008]. CXCR2 ligand (CXCL2) and CXCR4 ligand (CXCL12) are both constitutively expressed by osteoblast and endothelial cells in the bone marrow.…”

“…G-CSF reduces the number of osteoblasts which are a major source of CXCL12, while increasing expression of CXCR2 ligands by endothelial cells in the bone marrow [Semerad et al, 2002;Wengner et al, 2008].…”