Skip Navigation LinksHome > January 2007 - Volume 14 - Issue 1 > Regulation of neutrophil homeostasis
Current Opinion in Hematology:
Myeloid biology

Regulation of neutrophil homeostasis

Christopher, Matthew J; Link, Daniel C

Free Access
Article Outline
Collapse Box

Author Information

Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA

Correspondence to Daniel C. Link, MD, Division of Oncology, Department of Medicine, 660 S. Euclid Avenue, Campus Box 8007, Saint Louis, MO 63110, USA Tel: +1 314 362 8771; Fax: +1 314 362 9333; e-mail: dlink@im.wustl.edu

Collapse Box

Abstract

Purpose of review: Neutrophils are an essential component of the innate immune response and a major contributor to inflammation. Consequently, neutrophil number in the blood is tightly regulated. Herein, we review recent studies that have greatly advanced our understanding of the mechanisms controlling neutrophil homeostasis.

Recent findings: Accumulating evidence shows that stromal derived factor-1 (CXCL12) through interaction with its major receptor CXCR4 provides a key retention signal for neutrophils in the bone marrow. Granulocyte colony-stimulating factor induces neutrophil release from the bone marrow, in major part, by disrupting stromal derived factor-1/CXCR4 signaling. Granulocyte colony-stimulating factor expression is regulated by a novel feedback loop that senses neutrophil emigration into tissues. Specifically, engulfment of apoptotic neutrophils by tissue phagocytes initiates a cytokine cascade that includes interleukin-23, interleukin-17, and ultimately granulocyte colony-stimulating factor.

Summary: Granulocyte colony-stimulating factor plays a central role in the dynamic regulation of neutrophil production and release from the bone marrow in response to environmental stresses. Recent studies have begun to elucidate both the pathways linking neutrophil clearance to granulocyte colony-stimulating factor expression and the mechanisms by which the factor induces neutrophil release from the bone marrow. These studies may lead to novel strategies to modulate neutrophil responses in host defense and inflammation.

Abbreviations G-CSF: granulocyte colony-stimulating factor; G-CSFR: granulocyte colony-stimulating factor receptor; GM-CSF: granulocyte-macrophage colony stimulating factor; MMP: matrix metalloproteinase; SDF-1: stromal derived factor-1; WHIM: warts, hypogammaglobulinemia, infections, and myelokathexis.

Back to Top | Article Outline

Introduction

A key component of innate immunity, neutrophils are critical for host protection against bacterial and fungal pathogens. On the other hand, excessive neutrophil infiltration and activation contributes to tissue damage in such pathologic states as rheumatoid arthritis and adult respiratory distress syndrome. Consequently, neutrophil number in the blood is tightly regulated. Neutrophil homeostasis represents a balance between the production, release, and clearance of neutrophils from the circulation. This review will focus on recent studies that provide new insight into the molecular mechanisms by which neutrophil homeostasis is maintained in health and disease.

Back to Top | Article Outline

General features of neutrophil homeostasis

Under normal conditions, neutrophils are produced solely in the bone marrow by a process termed granulopoiesis. Neutrophils are released from the bone marrow to blood in a regulated fashion. In fact, at steady state, only a small fraction of the total bone marrow neutrophil pool is released into circulation. Mature neutrophils are rapidly cleared from the circulation, with a half-life of only 6–8 h. Importantly, under stress conditions, such as infection, peripheral blood neutrophil counts can rise significantly. This ‘emergency or stress granulopoiesis’ response is mediated by increased granulopoiesis and enhanced neutrophil release [1,2]. The signals regulating neutrophil emigration from the blood to tissue are relatively well understood and will not be covered in this review. Interested readers are referred to several excellent reviews on this topic [3,4].

Back to Top | Article Outline

Regulation of granulopoiesis

Granulocytic differentiation of hematopoietic stem cells is regulated by the coordinated expression of a number of key myeloid transcription factors, including PU.1, CCAAT enhancer binding protein (C/EBP) α, C/EBPϵ, and GFI-1. The contribution of these and other transcription factors to the regulation of granulopoiesis has been reviewed previously and will not be covered here [5].

To maintain normal neutrophil homeostasis, neutrophil proliferation and differentiation must be linked to environmental cues. Among the extracellular signals necessary for normal granulopoiesis, cytokine signaling plays a key role. The principle cytokine regulating granulopoiesis is granulocyte colony-stimulating factor (G-CSF), and it is widely used in the clinical setting to treat or prevent neutropenia. G-CSF stimulates granulopoiesis at several stages of granulocytic differentiation. It induces the commitment of multipotential progenitor cells down the myeloid lineage [6], stimulates the proliferation of granulocytic precursors, and reduces the average transit time through the granulocytic compartment [7]. In addition, as discussed in more detail below, it potently stimulates neutrophil release from the bone marrow. The biological effects of G-CSF are mediated through the G-CSF receptor (G-CSFR), a member of the hematopoietic (class I) cytokine receptor family. The importance of G-CSF in the regulation of basal granulopoiesis has been confirmed by the severe, but not absolute, neutropenia present in G-CSF−/− and G-CSFR−/− mice [8,9]. Similarly, humans expressing a dominant negative mutation in the G-CSFR exhibit profound neutropenia [10–12].

Though serum levels of G-CSF are often elevated during infection [13,14], the importance of G-CSF in regulating the stress granulopoiesis response is controversial. G-CSF−/− mice infected intravenously with Candida albicans or intraperitoneally with Listeria monocytogenes demonstrated a neutrophilia that matched that of wild type littermates, suggesting a nonessential role for G-CSF in mediating stress granulopoiesis [9,15]. In contrast, G-CSF−/− mice infected intravenously with L. monocytogenes demonstrated reduced neutrophil recruitment into the blood compared to wild type littermates [16]. In perhaps a more physiological model, we recently showed that neutrophil release is blunted in G-CSFR deficient mice following intratracheal injection of Pseudomonas aeruginosa (unpublished observations). These data suggest that G-CSF plays an important role in regulating neutrophil release in response to some, but not all, infections.

While these data support a primary role for G-CSF in granulopoiesis, it is worth noting that other hematopoietic cytokines – including IL-3, granulocyte-macrophage colony stimulating factor (GM-CSF), and IL-6 – stimulate granulopoiesis in vivo [17–19]. Further, systemic levels of these cytokines are often increased during infection, and IL-6 and GM-CSF are necessary for normal stress granulopoiesis responses in certain animal models of infection [16,20]. Mouse knockouts of GM-CSF, IL-3, and IL-6, however, exhibit no defect in basal granulopoiesis, suggesting that these cytokines are dispensable for neutrophil production [20–22].

Back to Top | Article Outline

General features of neutrophil trafficking from the bone marrow

The release of neutrophils from the bone marrow to the circulation contributes to the maintenance of neutrophil homeostasis and, as such, is a tightly regulated process. In the bone marrow, hematopoiesis is restricted to the extravascular space where dense cords of hematopoietic cells are interspersed among the venous sinuses [23]. To enter the circulation, hematopoietic cells must migrate through a vascular barrier that separates the hematopoietic compartment from the circulation. Bone marrow venous sinuses are the sites of leukocyte egress from the hematopoietic compartment. The sinus wall is a trilaminar structure composed of endothelial cells, a basement membrane, and a layer of adventitial cells [24,25]. Electron microscopy studies have demonstrated that there are numerous sites within the endothelial cell where the luminal and abluminal membranes are fused, forming structures referred to as diaphragmed fenestra [25,26]. It is through these fenestrations that cell egress occurs. Cellular migration across this barrier is selective in that only mature leukocytes are released from the bone marrow.

In mice at baseline only an estimated 1–2% of mature neutrophils are in the circulation, with the great majority of remaining neutrophils in the bone marrow [27]. Consequently, the bone marrow provides a large reserve of neutrophils that can be mobilized in response to infection or stress. A diverse group of agents can induce neutrophil release from the bone marrow, including cytokines, chemokines, leukotrienes, bacterial products, and other inflammatory mediators (e.g. complement factors) [1]. Most of these agents share the ability to directly activate neutrophils. The kinetics of neutrophil mobilization exhibited by these agents is highly variable, however, raising the possibility that their mechanisms of neutrophil release are distinct. For example, neutrophil mobilization by G-CSF peaks 4–6 h after administration, whereas peak levels are observed within a few minutes of IL-8 administration [28–30].

Back to Top | Article Outline

Adhesion molecules regulating neutrophil trafficking

Integrins and selectins are the major adhesion molecules regulating the trafficking of neutrophils. The role of these molecules in the emigration of neutrophils from the blood to sites of inflammation has been extensively studied (reviewed by Simon and Green [3]). Studies have begun to determine the importance of adhesion molecules in neutrophil egress from the bone marrow. Using a novel in-situ rat model of neutrophil release from the bone marrow, Burdon et al. [31•] showed that MIP-2 induced neutrophil release was enhanced when neutralizing antibodies to CD18 (β2-integrin subunit) were co-administered. In contrast, blockade of VLA-4 (α4 β1 integrin) function markedly inhibited neutrophil release. Finally, inhibition of L-selectin shedding had no effect on neutrophil release. These data suggested that β2 and β1-integrins may play contrasting roles in regulating neutrophil tracking in the bone marrow; whereas β2-integrins support neutrophil retention, β1-integrins are required for neutrophil egress.

Somewhat different conclusions are reached from the study of mice genetically deficient in these adhesion molecules. CD18 (β2-integrin) deficient mice display marked neutrophilia. Only a small component of this phenotype, however, appears to be secondary to a cell-intrinsic enhancement of neutrophil release from the bone marrow [32]. Conditional deletion of the α4-integrin in hematopoietic cells is associated with leukocytosis; no perturbation in neutrophil trafficking has been reported [33]. Finally, mice deficient in L-selectin have apparently normal neutrophil retention and release from the bone marrow [34,35].

Back to Top | Article Outline

Role of proteases in neutrophil mobilization

It has been proposed that hematopoietic proteases, in particular neutrophil proteases, play a role in regulating leukocyte trafficking from the bone marrow. Proteolytic enzymes can degrade extracellular matrix, cleave adhesion molecules, and influence cell–cell signaling by degrading receptors and ligands. Neutrophil mobilization by IL-8 is associated with increased levels of matrix metalloproteinase (MMP)-9 (gelatinase B) in the bone marrow. Similarly, MMP-9, neutrophil elastase (NE), and cathepsin G accumulate in the bone marrow during G-CSF treatment [36]. In-vitro experiments showed that these proteases are able to cleave several adhesion molecules thought to play an important role in regulating leukocyte trafficking in the bone marrow, including c-Kit, vascular cell adhesion molecule-1, and stromal derived factor-1 (SDF-1) [37–40]. To determine the biological significance of these proteases in G-CSF induced neutrophil mobilization, we studied transgenic mice lacking one or more of these proteases [41]. Surprisingly, neutrophil mobilization by G-CSF was normal in MMP-9 deficient mice, neutrophil elastase × cathepsin G deficient mice, or mice lacking dipeptidyl peptidase I, an enzyme required for the functional activation of all neutrophil serine proteases. Moreover, combined inhibition of neutrophil serine proteases and metalloproteinases had no significant effect on neutrophil mobilization. Clearly, these proteases are not required for neutrophil trafficking from the bone marrow. It is possible, however, that as yet unidentified proteases with overlapping function provide redundant pathways in neutrophil mobilization.

Back to Top | Article Outline

Regulation of neutrophil release by stromal derived factor-1/CXCR4 signaling

SDF-1 (CXCL12) is a CXC chemokine that was originally cloned from a bone marrow stromal cell line. The major receptor for SDF-1 is CXCR4, a G-protein coupled heptahelical receptor [42,43]. CXCR4 is broadly expressed on hematopoietic cells, including neutrophils. SDF-1 is a chemoattractant for neutrophils [44]. It also has been shown to regulate cell adhesion, survival, and proliferation [45–47].

There is accumulating evidence that SDF-1/CXCR4 signaling may regulate neutrophil trafficking in the bone marrow. First, SDF-1 is constitutively produced by stromal cells in the bone marrow [48]. Second, CXCR4 gene deletion in murine hematopoietic cells leads to constitutive neutrophil release [49]. Third, treatment with AMD3100, a selective antagonist of CXCR4, or treatment with CXCR4 blocking antibodies leads to the rapid mobilization of neutrophils in humans and mice [50,51]. These data support a model in which the constitutively high concentration of SDF-1 in the bone marrow provides a key retention signal for neutrophils in the bone marrow.

Consistent with this model, recent studies suggest that increased SDF-1/CXCR4 signaling may be responsible for the accumulation of neutrophils in the bone marrow observed in patients with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome. WHIM syndrome is a rare autosomal dominant disorder characterized, in part, by severe neutropenia despite normal to increased numbers of neutrophils in the bone marrow (a condition termed myelokathexsis). Genetic studies have identified heterozygous mutations of the CXCR4 gene in 20 of 22 patients with WHIM syndrome [52,53]. These mutations invariably result in the truncation of the carboxy-terminus of CXCR4 protein. Expression of the truncated CXCR4 protein in primary leukocytes or cell lines is associated with increased sensitivity to SDF-1. Together, these data suggest a model in which accentuated signaling by the truncated CXCR4 receptor leads to enhanced neutrophil retention in the bone marrow of patients with WHIM syndrome.

There is evidence that SDF-1/CXCR4 signaling may be disrupted during neutrophil mobilization by G-CSF. Daily treatment with G-CSF for 4–5 days is associated with marked neutrophilia that is due to both increased neutrophil production and enhanced neutrophil release [27]. Treatment with G-CSF induces a rapid decrease in the cell surface expression of CXCR4 [54•]. Levesque and colleagues showed that CXCR4 on hematopoietic progenitors is cleaved during G-CSF treatment, raising the possibility that CXCR4 also is cleaved on neutrophils [38]. We and others have shown that daily treatment with G-CSF also results in a significant decrease in SDF-1 expression in the bone marrow, with kinetics that mirror that of neutrophil mobilization [27,55]. SDF-1 is constitutively expressed at a high level by osteoblasts in the bone marrow. Through as yet unclear mechanisms, G-CSF potently inhibits osteoblast activity leading to decreased SDF-1 expression [55]. Importantly, through the study of transgenic mice expressing different G-CSFR mutants, we showed that the magnitude of neutrophil mobilization by G-CSF strongly correlates with the fall in SDF-1 protein expression in the bone marrow [27]. Collectively, these data suggest a model in which disruption of SDF-1/CXCR4 signaling is a key step in neutrophil mobilization by G-CSF (Fig. 1).

Figure 1
Figure 1
Image Tools

Disruption of SDF-1/CXCR4 signaling may also contribute to mobilization by certain chemokines. A recent study [56] showed that treatment of neutrophils with the CXC chemokine KC led to heterologous desensitization of CXCR4. This effect, however, is not observed with all chemokine receptors, suggesting that downregulation of SDF-1/CXCR4 signaling is not the only mechanism leading to neutrophil release [57].

Back to Top | Article Outline

Regulation of neutrophil clearance from the blood

In addition to release from the bone marrow, neutrophil homoeostasis is influenced by the clearance of neutrophils in the circulation. In absence of inflammation, circulating neutrophils are quickly turned over with an estimated half-life of 6–8 h. Surprisingly, G-CSF does not appear to regulate neutrophil clearance, as the half-life of neutrophils in the blood of G-CSF−/− mice is normal [9]. Though the mechanisms are poorly understood, senescent or damaged neutrophils are cleared primarily in the liver, spleen, or bone marrow [58]. Recent data suggest that SDF-1/CXCR4 signaling may contribute to the clearance of senescent neutrophils from the blood. CXCR4 expression increases on neutrophils as they age and may contribute to the preferential homing of senescent neutrophils to the bone marrow [44,59]. Consistent with this possibility, blocking antibodies to CXCR4 impedes neutrophil homing to the bone marrow [58,59]. Thus, SDF-1/CXCR4 signaling may play a dual role in regulating neutrophil homeostasis, both as a retention signal limiting the number of neutrophils released to the circulation and as a homing signal for clearing senescent neutrophils from the blood.

Back to Top | Article Outline

Coordination of neutrophil clearance with production and release

A recent study [60••] identified a novel feedback loop linking neutrophil clearance in tissues with neutrophil production and release from the bone marrow, providing a novel mechanism to maintain neutrophil homeostasis and a potential explanation for the neutrophilia associated with leukocyte adhesion deficiency (LAD). Type one LAD is secondary to the genetic deficiency of β2 integrins that results in impaired neutrophil emigration from the blood to sites of inflammation (reviewed by Bunting et al. [61]). In a series of elegant experiments, Stark et al. [60••] showed that ingestion of apoptotic neutrophil by tissue phagocytes initiates a cytokine cascade that ultimately regulates neutrophil production and release. Specifically, following ingestion of apoptotic neutrophils, phagocytes secrete IL-23 that, in turn, suppresses IL-17 expression in a subset of T lymphocytes. This decrease in IL-17 results in decreased systemic levels of G-CSF and ultimately reduced neutrophil production and release. Thus, the impaired emigration of β2-integrin deficient neutrophils to tissues fails to activate this negative feedback loop, resulting in neutrophilia.

Back to Top | Article Outline

Conclusion

A model summarizing our current understanding of the signals regulating neutrophil homeostasis is depicted in Fig. 2. G-CSF and SDF-1 signals play a central role in the dynamic regulation of neutrophil production and release in response to environmental stresses. This model suggests several questions. Is disruption of SDF-1/CXCR4 signaling a common mechanism by which all mobilizing agents induce neutrophil release? What are the mechanisms by which SDF-1 modulates neutrophil migration and adhesion? Finally, by what pathways does G-CSF decrease SDF-1 expression in the bone marrow? These studies may lead to novel strategies to modulate neutrophil responses in host defense and inflammation.

Figure 2
Figure 2
Image Tools
Back to Top | Article Outline

References and recommended reading

Back to Top | Article Outline

Papers of particular interest, published within the annual period of review, have been highlighted as:

Back to Top | Article Outline

• of special interest

Back to Top | Article Outline

•• of outstanding interest

Back to Top | Article Outline

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 62–64).

1 Starckx S, Van den Steen P, Wuyts A, et al. Neutrophil gelatinase B and chemokines in leukocytosis and stem cell mobilization. Leuk Lymphoma 2002; 43:233–241.

2 Link DC. Neutrophil homeostasis: a new role for stromal cell-derived factor-1. Immunol Res 2005; 32:169–178.

3 Simon SI, Green CE. Molecular mechanics and dynamics of leukocyte recruitment during inflammation. Annu Rev Biomed Eng 2005; 7:151–185.

4 Wagner J, Roth R. Neutrophil migration mechanisms, with an emphasis on the pulmonary vasculature. Pharmacol Rev 2000; 52:349–374.

5 Rosmarin AG, Yang Z, Resendes KK. Transcriptional regulation in myelopoiesis: Hematopoietic fate choice, myeloid differentiation, and leukemogenesis. Exp Hematol 2005; 33:131–143.

6 Richards MK, Liu F, Iwasaki H, et al. Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway. Blood 2003; 102:3562–3568.

7 Lord B, Bronchud M, Owens S, et al. The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo. Proc Natl Acad Sci U S A 1989; 86:9499–9503.

8 Liu F, Wu HY, Wesselschmidt R, et al. Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity 1996; 5:491–501.

9 Lieschke GJ, Grail D, Hodgson G, et al. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 1994; 84:1737–1746.

10 Dror Y, Ward AC, Touw IP, Freedman MH. Combined corticosteroid/granulocyte colony-stimulating factor (G-CSF) therapy in the treatment of severe congenital neutropenia unresponsive to G-CSF: Activated glucocorticoid receptors synergize with G-CSF signals. Exp Hematol 2000; 28:1381–1389.

11 Sinha S, Zhu QS, Romero G, Corey SJ. Deletional mutation of the external domain of the human granulocyte colony-stimulating factor receptor in a patient with severe chronic neutropenia refractory to granulocyte colony-stimulating factor. J Pediatr Hematol Oncol 2003; 25:791–796.

12 Druhan LJ, Ai J, Massullo P, et al. Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia. Blood 2004; 105:584–591.

13 Kawakami M, Tsutsumi H, Kumakawa T, et al. Levels of serum granulocyte colony-stimulating factor in patients with infections. Blood 1990; 76:1962–1964.

14 Cheers C, Haigh A, Kelso A, et al. Production of colony-stimulating factors (CSFs) during infection: separate determinations of macrophage-, granulocyte-, granulocyte-macrophage-, and multi-CSFs. Infect Immun 1988; 56:247–251.

15 Basu S, Hodgson G, Zhang HH, et al. ‘Emergency’ granulopoiesis in G-CSF-deficient mice in response to Candida albicans infection. Blood 2000; 95:3725–3733.

16 Zhan Y, Lieschke G, Grail D, et al. Essential roles for granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF in the sustained hematopoietic response of Listeria monocytogenes-infected mice. Blood 1998; 93:863–869.

17 Pojda Z, Tsuboi A. In vivo effects of human recombinant interleukin 6 on hemopoietic stem and progenitor cells and circulating blood cells in normal mice. Exp Hematol 1990; 18:1034–1037.

18 Metcalf D, Begley C, Williamson D, et al. Hemopoietic responses in mice injected with purified recombinant murine GM-CSF. Exp Hematol 1987; 15:1–9.

19 Metcalf D, Begley C, Johnson G, et al. Effects of purified bacterially synthesized murine multi-CSF (IL-3) on hematopoiesis in normal adult mice. Blood 1986; 68:46–57.

20 Kopf M, Baumann H, Freer G, et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 1994; 368:339–342.

21 Stanley E, Lieschke G, Grail D, et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of haemopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci U S A 1994; 91:5592–5596.

22 Nishinakamura R, Miyajima A, Mee P, et al. Hematopoiesis in mice lacking the entire granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 functions. Blood 1996; 88:2458–2464.

23 Yoder MC, Williams DA. Matrix molecule interactions with hematopoietic stem cells. Exp Hematol 1995; 23:961–967.

24 Inoue S, Osmond DG. Basement membrane of mouse bone marrow sinusoids shows distinctive structure and proteoglycan composition: a high resolution ultrastructural study. Anat Rec 2001; 264:294–304.

25 Campbell F. Ultrastructural studies of transmural migration of blood cells in the bone marrow of rats, mice and guinea pigs. Am J Anat 1972; 135:521–536.

26 Weiss L. Transmural cellular passage in vascular sinuses pf rat bone marrow. Blood 1970; 36:189–208.

27 Semerad CL, Liu F, Gregory AD, et al. G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 2002; 17:413–423.

28 Ulich TR, del Castillo J, Souza L. Kinetics and mechanisms of recombinant human granulocyte-colony stimulating factor-induced neutrophilia [published erratum appears in Am J Pathol 1989 Feb;134(2):236]. Am J Pathol 1988; 133: 630–638

29 Cohen AM, Zsebo KM, Inoue H, et al. In vivo stimulation of granulopoiesis by recombinant human granulocyte colony-stimulating factor. Proc Natl Acad Sci U S A 1987; 84:2484–2488.

30 Hechtman D, Cybulsky M, Fuchs H, et al. Intravascular IL-8. Inhibitor of polymorphonuclear leukocyte accumulation at sites of acute inflammation. J Immunol 1991; 147:883–892.

31• Burdon PC, Martin C, Rankin SM. The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner. Blood 2005; 105:2543–2548.

32 Forlow SB, Schurr JR, Kolls JK, et al. Increased granulopoiesis through interleukin-17 and granulocyte colony-stimulating factor in leukocyte adhesion molecule-deficient mice. Blood 2001; 98:3309–3314.

33 Scott LM, Priestley GV, Papayannopoulou T. Deletion of α4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing. Mol Cell Biol 2003; 23:9349–9360.

34 Robinson S, Frenette P, Rayburn H, et al. Multiple, targeted deficiencies in selectins reveal a predominant role for P-selectin in leukocyte recruitment. Proc Natl Acad Sci U S A 1999; 96:11425–11427.

35 Arbones M, Ord D, Ley K, et al. Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice. Immunity 1994; 1:247–260.

36 Levesque JP, Hendy J, Takamatsu Y, et al. Mobilization by either cyclophosphamide or granulocyte colony-stimulating factor transforms the bone marrow into a highly proteolytic environment. Exp Hematol 2002; 30:440–449.

37 Petit I, Szyper-Kravitz M, Nagler A, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4 [erratum appears in Nat Immunol 2002 Aug; 3(8):787]. Nat Immunol 2002; 3: 687–694.

38 Levesque JP, Hendy J, Takamatsu Y, et al. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest 2003; 111:187–196.

39 Levesque JP, Takamatsu Y, Nilsson SK, et al. Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood 2001; 98:1289–1297.

40 Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002; 109:625–637.

41 Levesque JP, Liu F, Simmons PJ, et al. Characterization of hematopoietic progenitor mobilization in protease-deficient mice. Blood 2004; 104:65–72.

42 Oberlin E, Amara A, Bachelerie F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 1996; 382:833–835.

43 Bleul CC, Farzan M, Choe H, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 1996; 382:829–833.

44 Nagase H, Miyamasu M, Yamaguchi M, et al. Cytokine-mediated regulation of CXCR4 expression in human neutrophils. J Leukoc Biol 2002; 71:711–717.

45 Peled A, Kollet O, Ponomaryov T, et al. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood 2000; 95:3289–3296.

46 Lataillade JJ, Clay D, Bourin P, et al. Stromal cell-derived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G(0)/G(1) transition in CD34(+) cells: evidence for an autocrine/paracrine mechanism. Blood 2002; 99:1117–1129.

47 Lataillade JJ, Clay D, Dupuy C, et al. Chemokine SDF-1 enhances circulating CD34(+) cell proliferation in synergy with cytokines: possible role in progenitor survival. Blood 2000; 95:756–768.

48 Aiuti A, Webb IJ, Bleul C, et al. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 1997; 185:111–120.

49 Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 1999; 10:463–471.

50 Liles WC, Broxmeyer HE, Rodger E, et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 2003; 102:2728–2730.

51 Broxmeyer HE, Orschell CM, Clapp DW, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. JEM 2005; 201:1307–1318.

52 Hernandez PA, Gorlin RJ, Lukens JN, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet 2003; 34:70–74.

53 Gorlin RJ, Gelb B, Diaz GA, et al. WHIM syndrome, an autosomal dominant disorder: clinical, hematological, and molecular studies. Am J Med Genet 2000; 91:368–376.

54• Kim HK, De La Luz Sierra M, Williams CK, et al. G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells. Blood 2006; 108:812–820.

55 Semerad CL, Christopher MJ, Liu F, et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 2005; 106:3020–3027.

56 Suratt BT, Petty JM, Young SK, et al. Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis. Blood 2004; 104:565–571.

57 Richardson R, Tokunaga K, Marjoram R, et al. Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization. J Biol Chem 2003; 278:15867–15873.

58 Suratt B, Young S, Lieber J, et al. Neutrophil maturation and activation determine anatomic site of clearance from circulation. Am J Physiol Lung Cell Mol Physiol 2001; 281:L913–L921.

59 Martin C, Burdon PC, Bridger G, et al. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 2003; 19:583–593.

60•• Stark MA, Huo Y, Burcin TL, et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 2005; 22:285–294. The authors describe a novel feedback mechanism linking neutrophil clearance with production and release.

61 Bunting M, Harris E, McIntyre T, et al. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands. Curr Opin Hematol 2002; 9:30–35.

Cited By:

This article has been cited 44 time(s).

New England Journal of Medicine
Mechanisms of disease: Acute lower respiratory tract infection
Mizgerd, JP
New England Journal of Medicine, 358(7): 716-727.

Journal of Immunology
Novel Role for Aldose Reductase in Mediating Acute Inflammatory Responses in the Lung
Ravindranath, TM; Mong, PY; Ananthakrishnan, R; Li, Q; Quadri, N; Schmidt, AM; Ramasamy, R; Wang, Q
Journal of Immunology, 183(): 8128-8137.
10.4049/jimmunol.0900720
CrossRef
Nature
Bv8 regulates myeloid-cell-dependent tumour angiogenesis
Shojaei, F; Wu, XM; Zhong, CL; Yu, LL; Liang, XH; Yao, J; Blanchard, D; Bais, C; Peale, FV; van Bruggen, N; Ho, C; Ross, J; Tan, M; Carano, RAD; Meng, YG; Ferrara, N
Nature, 450(): 825-U6.
10.1038/nature06348
CrossRef
Circulation Research
Open sesame! CXCR4 blockade recruits neutrophils into the plaque
Sainz, J; Sata, M
Circulation Research, 102(2): 154-156.
10.1161/CIRCRESAHA.107.170241
CrossRef
Febs Letters
Neutrophilia and elevated serum cytokines are implicated in glycogen storage disease type Ia
Kim, SY; Chen, LY; Yiu, WH; Weinstein, DA; Chou, JY
Febs Letters, 581(): 3833-3838.
10.1016/j.febslet.2007.07.013
CrossRef
Injury-International Journal of the Care of the Injured
The systemic inflammatory response induced by trauma is reflected by multiple phenotypes of blood neutrophils
Pillay, J; Hietbrink, F; Koenderman, L; Leenen, LPH
Injury-International Journal of the Care of the Injured, 38(): 1365-1372.
10.1016/j.injury.2007.09.016
CrossRef
Journal of Immunology
CLEC-2 Is a Phagocytic Activation Receptor Expressed on Murine Peripheral Blood Neutrophils
Kerrigan, AM; Dennehy, KM; Mourao-Sa, D; Faro-Trindade, I; Willment, JA; Taylor, PR; Eble, JA; Sousa, CRE; Brown, GD
Journal of Immunology, 182(7): 4150-4157.
10.4049/jimmunol.0802808
CrossRef
International Immunopharmacology
Maitake beta-glucan enhances granulopoiesis and mobilization of granulocytes by increasing G-CSF production and modulating CXCR4/SDF-1 expression
Ito, K; Masuda, Y; Yamasaki, Y; Yokota, Y; Nanba, H
International Immunopharmacology, 9(): 1189-1196.
10.1016/j.intimp.2009.06.007
CrossRef
Blood
Homeostasis of dendritic cells in lymphoid organs is controlled by regulation of their precursors via a feedback loop
Hochweller, K; Miloud, T; Striegler, J; Naik, S; Hammerling, GJ; Garbi, N
Blood, 114(): 4411-4421.
10.1182/blood-2008-11-188045
CrossRef
International Journal of Biochemistry & Cell Biology
Granulocyte colony-stimulating factor receptor: Stimulating granulopoiesis and much more
Liongue, C; Wright, C; Russell, AP; Ward, AC
International Journal of Biochemistry & Cell Biology, 41(): 2372-2375.
10.1016/j.biocel.2009.08.011
CrossRef
Journal of Immunology
Defective Regulation of CXCR2 Facilitates Neutrophil Release from Bone Marrow Causing Spontaneous Inflammation in Severely NF-kappa B-Deficient Mice
von Vietinghoff, S; Asagiri, M; Azar, D; Hoffmann, A; Ley, K
Journal of Immunology, 185(1): 670-678.
10.4049/jimmunol.1000339
CrossRef
Frontiers in Bioscience
Regulation of neutrophil apoptosis by cytokines, pathogens and environmental stressors
Maggini, J; Raiden, S; Salamone, G; Trevani, A; Geffner, J
Frontiers in Bioscience, 14(): 2372-2385.
10.2741/3384
CrossRef
Journal of Cellular and Molecular Medicine
Cell biology and clinical promise of G-CSF: immunomodulation and neuroprotection
Xiao, BG; Lu, CZ; Link, H
Journal of Cellular and Molecular Medicine, 11(6): 1272-1290.
10.1111/j.1582-4934.2007.00101.x
CrossRef
Journal of the National Comprehensive Cancer Network
Neutrophil Biology and the Next Generation of Myeloid Growth Factors
Dale, DC
Journal of the National Comprehensive Cancer Network, 7(1): 92-98.

Journal of Hepatology
Necrotic foci, elevated chemokines and infiltrating neutrophils in the liver of glycogen storage disease type Ia
Kim, SY; Weinstein, DA; Starost, MF; Mansfield, BC; Chou, JY
Journal of Hepatology, 48(3): 479-485.
10.1016/j.jhep.2007.11.014
CrossRef
Translational Research
Beyond angiogenesis: the role of endothelium in the bone marrow vascular niche
Colmone, A; Sipkins, DA
Translational Research, 151(1): 1-9.
10.1016/j.trsl.2007.09.003
CrossRef
Journal of Immunological Methods
Changes in the ratio between FPR and FPRL1 triggered superoxide production in human neutrophils - A tool in analysing receptor specific events
Fu, HM; Karlsson, J; Bjorkman, L; Stenfeldt, AL; Karlsson, A; Bylund, J; Dahgren, C
Journal of Immunological Methods, 331(): 50-58.
10.1016/j.jim.2007.11.005
CrossRef
American Journal of Respiratory and Critical Care Medicine
Evidence of Dysfunction of Endothelial Progenitors in Pulmonary Arterial Hypertension
Toshner, M; Voswinckel, R; Southwood, M; Al-Lamki, R; Howard, LSG; Marchesan, D; Yang, J; Suntharalingam, J; Soon, E; Exley, A; Stewart, S; Hecker, M; Zhu, ZP; Gehling, U; Seeger, W; Pepke-Zaba, J; Morrell, NW
American Journal of Respiratory and Critical Care Medicine, 180(8): 780-787.
10.1164/rccm.200810-1662OC
CrossRef
Histology and Histopathology
Role of neutrophil-derived matrix metalloproteinase-9 in tissue regeneration
Heissig, B; Nishida, C; Tashiro, Y; Sato, Y; Ishihara, M; Ohki, M; Gritli, I; Rosenkvist, J; Hattori, K
Histology and Histopathology, 25(6): 765-770.

Journal of Periodontology
Effects of periodontal therapy on glycemic control and inflammatory markers
O'Connell, PAA; Taba, M; Nomizo, A; Freitas, MCF; Suaid, FA; Uyemura, SA; Trevisan, GL; Novaes, AB; Souza, SLS; Palioto, DB; Grisi, MFM
Journal of Periodontology, 79(5): 774-783.
10.1902/jop.2008.070250
CrossRef
Journal of Immunology
Homeostatic regulation of blood neutrophil counts
von Vietinghoff, S; Ley, K
Journal of Immunology, 181(8): 5183-5188.

Experimental Eye Research
CXCR4 but not CXCR7 is mainly implicated in ocular leukocyte trafficking during ovalbumin-induced acute uveitis
Zhang, ZL; Zhong, WW; Hall, MJ; Kurre, P; Spencer, D; SkinnerA, A; O'Neill, S; Xia, ZW; Rosenbaum, JT
Experimental Eye Research, 89(4): 522-531.
10.1016/j.exer.2009.05.012
CrossRef
Biochemical and Biophysical Research Communications
Interleukin-1 beta mediates LPS-induced inhibition of apoptosis in retinoic acid-differentiated HL-60 cells
Marshall, JC; Jia, SH; Parodo, J; William, R; Watson, G
Biochemical and Biophysical Research Communications, 369(2): 532-538.
10.1016/j.bbrc.2008.02.044
CrossRef
Veterinary Clinics of North America-Equine Practice
Peripheral blood leukocytes
Carrick, JB; Begg, AP
Veterinary Clinics of North America-Equine Practice, 24(2): 239-+.
10.1016/j.cveq.2008.05.003
CrossRef
Cell Proliferation
A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia
Scholz, M; Ackermann, M; Engel, C; Emmrich, F; Loeffler, M; Kamprad, M
Cell Proliferation, 42(6): 813-822.
10.1111/j.1365-2184.2009.00638.x
CrossRef
Journal of Immunology
Interacting Neuroendocrine and Innate and Acquired Immune Pathways Regulate Neutrophil Mobilization from Bone Marrow following Hemorrhagic Shock
Liu, YJ; Yuan, YZ; Li, YH; Zhang, J; Xiao, GZ; Vodovotz, Y; Billiar, TR; Wilson, MA; Fan, J
Journal of Immunology, 182(1): 572-580.

International Journal of Hematology
Guidelines for safety management of granulocyte transfusion in Japan
Ohsaka, A; Kikuta, A; Ohto, H; Ohara, A; Ishida, A; Osada, K; Tasaki, T; Kamitamari, A; Iwai, A; Kai, S; Maekawa, T; Hoshi, Y
International Journal of Hematology, 91(2): 201-208.
10.1007/s12185-010-0506-z
CrossRef
Immunologic Research
Understanding the multiple functions of Gr-1(+) cell subpopulations during microbial infection
Egan, CE; Sukhumavasi, W; Bierly, AL; Denkers, EY
Immunologic Research, 40(1): 35-48.
10.1007/s12026-007-0061-8
CrossRef
Journal of Leukocyte Biology
An age-associated increase in pulmonary inflammation after burn injury is abrogated by CXCR2 inhibition
Nomellini, V; Faunce, DE; Gomez, CR; Kovacs, EJ
Journal of Leukocyte Biology, 83(6): 1493-1501.
10.1189/jlb.1007672
CrossRef
Cell Proliferation
Pharmacokinetic and pharmacodynamic modelling of the novel human granulocyte colony-stimulating factor derivative Maxy-G34 and pegfilgrastim in rats
Scholz, M; Engel, C; Apt, D; Sankar, SL; Goldstein, E; Loeffler, M
Cell Proliferation, 42(6): 823-837.
10.1111/j.1365-2184.2009.00641.x
CrossRef
European Urban and Regional Studies
Introduction: Social innovation and governance in European cities - Urban development between path dependencyand radical innovation
Moulaert, F; Martinelli, F; Gonzalez, S; Swyngedouw, E
European Urban and Regional Studies, 14(3): 195-209.
10.1177/0969776407077737
CrossRef
Proceedings of the National Academy of Sciences of the United States of America
Activation of critical, host-induced, metabolic and stress pathways marks neutrophil entry into cystic fibrosis lungs
Makam, M; Diaz, D; Laval, J; Gernez, Y; Conrad, CK; Dunn, CE; Davies, ZA; Moss, RB; Herzenberg, LA; Herzenberg, LA; Tirouvanziam, R
Proceedings of the National Academy of Sciences of the United States of America, 106(): 5779-5783.
10.1073/pnas.0813410106
CrossRef
Blood
CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions
Eash, KJ; Means, JM; White, DW; Link, DC
Blood, 113(): 4711-4719.
10.1182/blood-2008-09-177287
CrossRef
Veterinary Immunology and Immunopathology
Temporal aspects of laminar gene expression during the developmental stages of equine laminitis
Noschka, E; Vandenplas, ML; Hurley, DJ; Moore, JN
Veterinary Immunology and Immunopathology, 129(): 242-253.
10.1016/j.vetimm.2008.11.002
CrossRef
Pediatric Blood & Cancer
A molecular classification of congenital neutropenia syndromes
Boxer, LA; Newburger, PE
Pediatric Blood & Cancer, 49(5): 609-614.
10.1002/pbc.21282
CrossRef
Sparking Signals: Kinases As Molecular Signal Transducers and Pharmacological Drug Targets in Inflammation
Migration, cell-cell interaction, and adhesion in the immune system
Gunzer, M
Sparking Signals: Kinases As Molecular Signal Transducers and Pharmacological Drug Targets in Inflammation, 3(): 97-137.

Acta Reumatologica Portuguesa
Neutrophils: Warriors and Commanders in Immune Mediated Inflammatory Diseases
Cascao, R; Rosario, HS; Fonseca, JE
Acta Reumatologica Portuguesa, 34(): 313-326.

Kidney International
Mycophenolic acid suppresses granulopoiesis by inhibition of interleukin-17 production
von Vietinghoff, S; Ouyang, H; Ley, K
Kidney International, 78(1): 79-88.
10.1038/ki.2010.84
CrossRef
Journal of Clinical Investigation
CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow
Eash, KJ; Greenbaum, AM; Gopalan, PK; Link, DC
Journal of Clinical Investigation, 120(7): 2423-2431.
10.1172/JCI41649
CrossRef
Cancer
Neutropenia in 6 ethnic groups from the Caribbean and the US
Grann, VR; Bowman, N; Joseph, C; Wei, Y; Horwitz, MS; Jacobson, JS; Santella, RP; Hershman, DL
Cancer, 113(4): 854-860.
10.1002/cncr.23614
CrossRef
Circulation
Clinical Trial of Doxycycline for Matrix Metalloproteinase-9 Inhibition in Patients With an Abdominal Aneurysm Doxycycline Selectively Depletes Aortic Wall Neutrophils and Cytotoxic T Cells
Lindeman, JHN; Abdul-Hussien, H; van Bockel, JH; Wolterbeek, R; Kleemann, R
Circulation, 119(): 2209-2216.
10.1161/CIRCULATIONAHA.108.806505
CrossRef
Plos One
Cyclic AMP Responsive Element Binding Proteins Are Involved in 'Emergency' Granulopoiesis through the Upregulation of CCAAT/Enhancer Binding Protein beta
Hirai, H; Kamio, N; Huang, G; Matsusue, A; Ogino, S; Kimura, N; Satake, S; Ashihara, E; Imanishi, J; Tenen, DG; Maekawa, T
Plos One, 8(1): -.
ARTN e54862
CrossRef
Journal of Leukocyte Biology
Localized bacterial infection induces systemic activation of neutrophils through Cxcr2 signaling in zebrafish
Deng, Q; Sarris, M; Bennin, DA; Green, JM; Herbomel, P; Huttenlocher, A
Journal of Leukocyte Biology, 93(5): 761-769.
10.1189/jlb.1012534
CrossRef
Cell Stress & Chaperones
Stress-induced effects, which inhibit host defenses, alter leukocyte trafficking
Zieziulewicz, TJ; Mondal, TK; Gao, DH; Lawrence, DA
Cell Stress & Chaperones, 18(3): 279-291.
10.1007/s12192-012-0380-0
CrossRef
Back to Top | Article Outline
Keywords:

CXCR4; granulocyte colony-stimulating factor; leukocyte trafficking; neutrophils; stromal-derived factor-1; SDF-1

© 2007 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.