Current Opinion in Hematology:
Regulation of neutrophil homeostasis
Christopher, Matthew J; Link, Daniel C
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: email@example.com
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.
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.
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].
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 .
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 , stimulates the proliferation of granulocytic precursors, and reduces the average transit time through the granulocytic compartment . 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 . 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].
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 . 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 . 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) . 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].
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 ). 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 . Conditional deletion of the α4-integrin in hematopoietic cells is associated with leukocytosis; no perturbation in neutrophil trafficking has been reported . Finally, mice deficient in L-selectin have apparently normal neutrophil retention and release from the bone marrow [34,35].
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 . 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 . 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.
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 . 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 . Second, CXCR4 gene deletion in murine hematopoietic cells leads to constitutive neutrophil release . 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 . 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 . 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 . 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 . 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).
Disruption of SDF-1/CXCR4 signaling may also contribute to mobilization by certain chemokines. A recent study  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 .
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 . Though the mechanisms are poorly understood, senescent or damaged neutrophils are cleared primarily in the liver, spleen, or bone marrow . 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.
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. ). 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.
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.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 62–64).
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CXCR4; granulocyte colony-stimulating factor; leukocyte trafficking; neutrophils; stromal-derived factor-1; SDF-1
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