Page 196 - Hematology_ Basic Principles and Practice ( PDFDrive )

148 Part II Cellular Basis of Hematology

to recruitment of HSPCs to the circulation (reviewed by Golan they are the first line of defense upon pathogen infiltration. During
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et al ). Accordingly, S1P concentrations in the plasma were rapidly steady-state homeostasis, mobilization of neutrophils from the BM
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increased following both G-CSF and AMD3100 treatments in mice, occurs at a dramatic rate of about 10 cells in humans and 10 in
as well as expression of its receptor S1P 1 on HSPCs (reviewed by mice per day, and they are characterized by a very short life span of
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Golan et al ). By utilizing mice with reduced S1P levels, or lacking about 12 h in mice. At baseline, the great majority (>98% in mice)
the S1P 1 receptor, Golan et al (2012) showed a reduced capacity of neutrophils are located in the BM, given a reservoir of neutrophils
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to mobilize upon G-CSF or AMD3100 treatments. Bendall et al to respond to stress conditions such as infections (reviewed by Day
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(2013) found that manipulation of the S1P/S1P 1 axis may be used to and Link ). During the acute phase of inflammation, neutrophils are
improve clinical mobilization protocols. As suggested by Bendall and the first leukocytes to migrate from the circulation to sites of infection
colleagues, activation of S1P 1 by a specific agonist during AMD3100 following a gradient of inflammatory stimuli, where they eradicate
administration led to increased levels of mobilized stem cells that the pathogens and are eventually cleared by macrophages. During
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are harvested for BM transplantation (reviewed by Golan et al ). homeostasis, neutrophils are maintained through a balance between
Furthermore, S1P was shown to induce SDF-1 secretion from BM their production in the BM, release through the endothelial barrier
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MSPCs and endothelial cells, followed by SDF-1 release from the to the circulation, and clearance from the circulation. Neutrophils
BM to the peripheral blood, adding another regulatory aspect for are key regulators of HSPC mobilization via HGF secretion, ROS
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HSPC mobilization (reviewed by Golan et al ). Altogether, recent signaling, and proteolytic enzymes. The chemokine CXCL2 is a
data suggest that additional chemoattractive compounds, such as potent chemoattractant of neutrophils, and it is known to play a
S1P, mediate egress and recruitment of HSPCs from the BM to the crucial role in the emigration of activated neutrophils from the BM,
circulation by regulating the SDF-1/CXCR4 axis. indirectly inducing HSPC mobilization. In addition, the major
mediators of neutrophil driving power for HSPC mobilization are
proteolytic enzymes (e.g., MMP9), which are released by activated
The Dynamic Brain–Bone–Blood Triad neutrophils into the BM microenvironment and periphery. These
proteolytic enzymes interfere with the SDF-1/CXCR4 retention
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The brain–bone–blood triad is composed of the nervous system, signal that preserves HSPCs in their BM niches, enabling their
bone-lining osteoblasts, and the hematopoietic system. The nervous subsequent recruitment from the BM to the blood. The requirement
system, a major regulator of the mammalian body that interacts with of neutrophils and G-CSF–induced HSPC mobilization was sup-
the immune system directly as well as indirectly, influences both ported by a study in 2012 showing that G-CSF mediated neutrophil
bone- and blood-forming stem and progenitor cells. The mammalian expansion in the BM of mice. In addition, G-CSF induced apoptosis
nervous system regulates the immune system during homeostasis as of MSPCs and osteoblasts through increased ROS production and
well as acute physiologic conditions, for example, during mental reduced expression of retention factors in the BM, including SDF-
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stress as part of the “fight-or-flight” response. The importance of 1. Depletion of activated neutrophils in mice by administration of
the nervous system for HSPC mobilization has been determined by neutralizing antibodies led to attenuation of G-CSF–mobilization
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establishing mice lacking catecholaminergic activity, which display effects. Although ROS generation in neutrophils is critical during
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an inability to induce HSPC mobilization by G-CSF. Adrenergic eradication of pathogens and is involved in the apoptotic processes,
stimulation suppresses bone-lining osteoblasts, causing a significant it also serves as a common signaling mediator. Except for ROS
reduction in SDF-1 production and leading to detachment of HSPCs generation in activated neutrophils, ROS signaling is a key intrinsic
from their BM niches. Katayama et al (2006) showed that G-CSF cellular mechanism during HSPC differentiation and recruitment to
administration in mice lacking catecholaminergic activity does not the periphery. Dar et al (2011) demonstrated that inhibition of ROS
result in osteoblast suppression, BM SDF-1 downregulation or subse- by the antioxidant N-acetyl cysteine could preferentially attenuate
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quent HSPC mobilization. Concomitantly, Spiegel et al (2008) have AMD3100-induced mobilization of murine HSPCs, suggesting that
also shown a role for the nervous system in hematopoiesis, not only ROS signaling is involved in rapid HSPC motility and egress. Tesio
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indirectly through its effects on bone-lining osteoblasts, but also et al (2011) found that granulocytes (e.g., neutrophils), activated
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through a direct effect on HSPC (reviewed by Spiegel et al ). In this by repeated G-CSF stimulations, release HGF. HGF in turn binds
regard, it was demonstrated that primitive human progenitor cells to its receptor c-Met on the HSPCs themselves, triggering mTOR/
express β 2 adrenergic receptors as well as dopamine receptors. These ROS signaling as part of the HSPC mobilization process (reviewed
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receptors are upregulated during G-CSF-induced mobilization of by Ludin et al ). It is therefore not surprising that blocking c-Met,
+
−
+
immature human CD34 cells, as well as on primitive CD34 CD38 mTOR, or ROS leads to inhibition of G-CSF–induced HSPC
cells, suggesting a role of sympathetic stimulation in inducing HSPC mobilization, while HGF administration induces their mobiliza-
mobilization. β 2 -Adrenergic stimulation by norepinephrine adminis- tion. Of note, Dar et al (2011) showed that inhibition of ROS by
tration in mice results in increased numbers of circulating HSPCs, N-acetyl cysteine not only reduces AMD3100-induced mobilization
while administration of β 2 -adrenergic antagonists reduced peripheral of HSPCs, but also reduces the induction of SDF-1 release by BM
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blood numbers (reviewed by Spiegel et al ). Interestingly, there are stromal and endothelial cells. These studies identified a cross-talk
daily oscillations of circulating murine HSPCs, peaking 5 h after the between SDF-1/CXCR4 via ROS signaling, which is essential for
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initiation of light in parallel to reduced BM SDF-1 levels. Thus the HSPC egress and mobilization (reviewed by Ludin et al ). Col-
physiologic egress of BM HSPCs into the circulation is not random lectively, results taken from different studies support the claim that
but follows daily circadian oscillations. These oscillations are depen- neutrophils are key elements in G-CSF–induced HSPC mobilization,
dent on the sympathetic neurotransmitter, norepinephrine, through as shown by HGF secretion, release of proteolytic enzymes, suppres-
the β 3 -adrenergic receptors expressed by BM stromal cells, leading sion of osteoblasts, and increased ROS generation. The mechanism
to downregulation of SDF-1 in the BM, and subsequently reducing of HSPC and neutrophil mobilization is summarized in Fig. 14.2.
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HSPC BM retention. Although all players of the brain–bone–blood
triad are linked and mutually regulated, much is unknown with
regard to the specific molecular mechanisms of this dynamic regula- Neutrophil Retention and Egress: The Essential Role of
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tion (reviewed by Spiegel et al ). SDF-1/CXCR4 and CXCL2/CXCR2 Signaling
Involvement of Bone Marrow Neutrophils in Stem and Accumulating evidence suggests that the SDF-1/CXCR4 axis
regulates neutrophil retention. SDF-1 is a chemoattractant not only
Progenitor Cell Mobilization for HSPCs, but also for many hematopoietic cell types, including
neutrophils. BM neutrophils and neutrophil precursors express low
Neutrophils are the most abundant myeloid leukocytes in mammals but visible levels of surface CXCR4 and high intracellular levels,
and are an essential component of the innate immune system, as suggesting an internalization of CXCR4 in vivo (reviewed by Day