Stimulation to leave the bone marrow occurs during inflammation or infection by the presence of chemoattractant factors as leukotriene LTB4, complement factor C5a, CXCL8 and intrinsic regulation factors like G-CSF, but recent findings describe that also circadian rhythms can contribute to neutrophil recruitmen from the bone marrow[ 43 ]. Under homeostatic conditions, G-CSF is the main regulator release of neutrophils. During maturation, G-CSF receptors maintain highly expressed on the surface of neutrophils[ 44 ], as well as on bone marrow stromal cells.
G-CSF also functions in another bone marrow interaction with neutrophils. Bone marrow endothelial cells express vascular cell adhesion molecule 1 VCAM-1 , which interact with the integrin very late antigen-4 on neutrophils. In summary, G-CSF stimulates bone marrow endothelial cells in several ways to down regulate their neutrophil homing receptors and increase the expression of ligands inducing neutrophil release.
After release, neutrophils can follow the gradient of chemoattractants into the tissues. P-selectins and E-selectins induced on endothelial cells will interact with PSGL-1, L-selectin and CD44 on neutrophils, mediating rolling and activation of the neutrophil integrins at the site of maximal chemokine concentration.
These integrins then interact with ICAM-1 molecules on the endothelial cells, causing neutrophil arrest. Adhesion strengthening occurs with subsequent spreading of the neutrophil, resulting in intravascular crawling.
The chemotactic process and the chemoattractant gradient both lead to a cytoskeletal rearrangement, necessary for the spreading and transmigration[ 51 ]. The leukocyte adhesion cascade is described in detail elsewhere and this information can be found in[ 49 ]. Once in the tissues, neutrophils are more prone to phagocytosis than blood neutrophils. As transmigration is partly mediated by fusion of secretory vesicles with the neutrophil membrane, several surface membrane receptors are added to the membrane as well as other functional proteins like chemoattractant and phagocytosis receptors.
Priming can be described as a resting state of a neutrophil but with a functional response e. Priming affects the neutrophil cytoskeletal organization to reduce deformability in order to retain in capillary beds[ 54 ]. In vitro , priming and subsequent shape change has been shown to be reversible[ 55 ], but there is limited data on the effects of priming on neutrophil kinetics in vivo.
De-priming should protect the systemic circulation from the potentially damaging effects of primed cells, for example because of the produced H 2 O 2 , a marker of primed or activated neutrophils. Mixed venous blood blood before the pulmonary circulation has higher H 2 O 2 compared with arterial blood blood after the pulmonary circulation , suggesting the lung to be the de-priming compartment[ 57 ].
De-priming may have effects on the life span of the neutrophil, as priming can lead to neutrophil-mediated tissue damage and therefore these neutrophils are phagocytosed by macrophages early in the inflammatory response[ 58 ]. Depriming may thus give an alternative way of clearance of harmful neutrophils in inflammatory responses[ 55 ]. Once activated in the tissues, transcriptional activity of neutrophils is up regulated, in part mediated by local G-CSF production, resulting in the production of cytokines[ 2 ].
Also, the neutrophil will start phagocytosing microorganisms, degranulate, activate the oxidative metabolism intracellularly and will finally undergo apoptosis. Degranulation is one of the first steps of neutrophil activation and is initiated during transmigration.
The components of the different granules are well known and are described elsewhere[ 59 , 60 ]. Not only anti-microbial proteins are stored in these compartments, but also proteases, components of the respiratory burst oxidase described below and a wide range of receptors, extracellular matrix proteins and soluble mediators of inflammation[ 61 ].
Soluble inflammatory factors are for example chemotactic proteins[ 62 , 63 ], inducers of vascular permeability changes[ 64 ] and antigen presenting cell-activators[ 65 ]. Degranulation transforms the neutrophil from passively circulating to being an effector cell of the innate immune system[ 60 ].
Upon activation of the neutrophil, also the oxidative metabolism of the cell is activated. Neutrophils are very effective at the generation of ROS, a process called the oxygen metabolism or the respiratory burst. Some components are stored in storage sites, like secondary granules, which associate with the oxidase complex after fusion of these storage sites with the membrane or with phagosomes[ 59 ]. These ROS serve as highly effective antimicrobial agents but are also highly damaging the host as the produced components are highly reactive.
ROS producing neutrophils are rapidly cleared by macrophages. An extend in the antimicrobial activity of the neutrophil is the formation of neutrophil extracellular traps NETs [ 66 ]. The formation of NETs is a result of nuclear swelling and dissolved chromatin. Along with the nuclear swelling, granules are also disintegrated and as a result, large strands of unpacked DNA are extruded from the cell, carrying along proteins from granules and from the cytosol.
At this time, already 24 different neutrophil proteins are associated with NETs, which are primarily proteins from primary granules such as MPO and elastase , secondary granules e. NETs have been shown to trap microorganisms and promote interaction with the granule proteins, resulting in microbial recognition, antimicrobial activity and tissue remodeling. NET formation is a cell-death dependent process, also influencing the life span of neutrophils[ 66 , 68 ].
In addition to being harmful for microbes, the proteins that neutrophils secrete also damage the host tissue. Therefore it is important to control the influx of neutrophils to prevent excessive tissue damage. Neutrophil influx is controlled by several negative feedback loops at different stages of the inflammatory response. For example during the chemotactic process, it has been described that after a first encounter with CXCL8, neutrophils are desensitized to additional chemotactic signals[ 69 , 70 ].
Intracellularly, there are proteins recruiting phosphotyrosine phosphatases, which deactivate receptors on the surface. For example suppressor of cytokine signaling 3 down regulates G-CSF receptor signaling by blocking the phosphotyrosine on the activated receptor thereby preventing the interaction with STAT3. Extracellularly, neutrophils and macrophages partner in the termination of inflammation[ 71 ]. The receptor Chem R23 on macrophages, DCs and endothelial cells mediates activation of macrophages that enhances the phagocytic capacity of macrophages for uptake of apoptotic neutrophils.
Neutrophil apoptosis itself is a specific process with different signals triggering apoptosis via different pathways. This process is described in detail elsewhere[ 73 , 74 ].
Importantly, phagocytosis by macrophages reduces the risk of necrotic neutrophil death and down regulates the local G-CSF production to limit neutrophil activation[ 1 ]. Other deactivating processes are granule-proteins like LL and cathepsin G that stimulate rolling monocytes to migrate into the inflamed tissue. Neutrophil-derived proteins then stimulate the extravasated monocytes to maturate into macrophages and subsequently phagocytose apoptotic neutrophils. The macrophages in turn release anti-inflammatory mediators such as IL, further limiting the damage neutrophils do to host tissues[ 71 ].
Importance of these deactivating signals is seen in clinical settings such as cystic fibrosis, in which neutrophils are insensitive to signals as IL and corticoids[ 75 , 76 ]. For a long time, neutrophils were thought to only be recruited to the inflamed tissue, act as phagocytic cells, release lytic enzymes and produce ROS, after which they were cleared. However, additional functions of neutrophils in inflammatory sites have recently been described.
First of all, neutrophils were shown to express genes encoding inflammatory mediators[ 2 ]. Secondly, neutrophils were found to produce anti-inflammatory molecules and factors promoting the resolution of inflammation, as described above and elsewhere[ 56 , 77 ] and thirdly, neutrophils were shown to engage in interactions with different cells of the immune system[ 20 ]. These new insights are very important for our understanding of inflammatory diseases, their resolution and possibility of neutrophils as targets to modulate immunity.
In vitro interactions with neutrophils have been shown for monocytes[ 78 ], macrophages, DCs, natural killer NK cells, lymphocytes and mesenchymal stem cells in the tissues and were reviewed by[ 79 ] Figure 2. Also, crosstalk with platelets[ 80 ] and regulatory T cells are described[ 81 ]. Subsequently, mature DCs induce T cell proliferation and polarization towards a Th1 response. Deactivated DCs showed a reduced phagocytic activity, thereby preventing the phagocytosis of neutrophils.
Second, an interaction was unraveled between neutrophils and NK cells. Neutrophils are required both in the bone marrow as well as in the peripherial development of NK cells[ 83 ]. NK cells can in turn promote neutrophil survival, expression of activation markers, priming of ROS production and cytokine synthesis[ 84 ].
These effects have only been described for neutrophils in vitro , so further in vivo investigation is needed, but it gives new insights in the expanding functions of inflammatory site neutrophils. The importance of these additional functions is still elusive. A third interaction is reported for neutrophils and lymphocytes. Neutrophils also play an important role in B-cell help where they can even induce class switching of B-cells, a property solely assigned to T-cells[ 20 ].
The next interaction described is the crosstalk with platelets. In transfusion-related acute lung injury, the leading cause of death after transfusion therapy, activated platelets were described to induce the formation of NETs[ 80 ].
In another study, platelet were suggested to bind to neutrophils in the lungs, with subsequent activation of neutrophils by platelet toll-like receptor TLR 4[ 87 ].
In order to induce this response, cell-cell contact between the apoptotic neutrophil and monocytes was required[ 78 ]. After leaving the bone marrow, the neutrophil becomes part of one of the two compartments found in blood: the circulating pool and the marginated pool. The circulating pool consists of neutrophils flowing freely through vascular spaces and the marginated pool consists of neutrophils adhered to the endothelium of capillaries and post capillary venules, often in the lung, liver and spleen[ 15 ].
Already in , Cohnheim observed cells in a marginal position along venule walls. This gave rise to the hypothesis that a marginated pool should exist. Next, it was found that leukocytes circulate freely in the blood, then adhere to the vascular endothelium, especially in sites where the blood flow is slow and then re-enter the circulation in a continuously exchanging process[ 88 ]. The relative size of the marginated and circulating pool however, can be affected during exercise or induced by adrenaline or drugs Figure 3.
It has been suggested that during infection the marginated pool is minimized, while the freely circulating pool becomes larger[ 89 ]. The marginated pool consists of neutrophils adhered to the endothelium of capillaries and postcapillary venules, often in the lung, liver and spleen. The bone marrow has also been suggested as a margination site[ 90 ].
Margination means a prolonged transit through these specific organs, resulting in an intravascular neutrophil pool. The lung has been a controversial margination site. Some data suggest that the lung is the predominant site of margination[ 91 ], but this has been called into question by others[ 92 ].
Interestingly, different neutrophil types localized in different organs[ 93 ]. Suratt et al [ 93 ] showed that mature peripheral blood neutrophils localize to the liver, bone marrow and to a lesser extent to the spleen. Younger marrow-derived neutrophils prefer to home back to the bone marrow, a process that will be described below, and inflammatory peritoneal neutrophils prefer the liver and the lungs.
The biodistribution of inflammatory neutrophils might be non-comparable with homeostatic conditions as these neutrophils are different in surface expression of receptors and in functioning. Apoptotic neutrophils are not detected in normal circulation, so the need for an efficient removal system is evident, as 10 11 neutrophils are believed to be produced and removed every day. Surface receptor expression is highly dynamic upon infection, but receptor expression also changes upon aging.
As neutrophils become senescent, expression of a receptor for chemotaxis, CXCR2, decreases, while the expression of a chemokine receptor, CXCR4, increases[ 77 , 94 ]. CXCR4 thus is not only a signal to retain neutrophils in the bone marrow, but is also acting on homing senescent cells to the marrow for destruction. CXCR4 expression is up regulated just before apoptosis and after homing to the bone marrow, the neutrophils will undergo apoptosis and are subsequently phagocytosed by stromal macrophages, which are present in the hematopoietic cords[ 73 , 95 ].
Furze et al [ 96 ] showed that in mice, about one third of In-labeled neutrophils were cleared via bone marrow stromal macrophages. Before, stromal macrophages were only known for the removal of cellular debris and non-productive B cells[ 97 ].
Homing neutrophils must actively migrate through the bone marrow endothelium, a process that is not possible for apoptotic neutrophils.
Neutrophils also home back to the bone marrow while the liver and spleen also remove circulating neutrophils. Furze et al [ 96 ] showed that phagocytosis of neutrophils in the bone marrow stimulates G-CSF production which in turn induces neutrophil production in the bone marrow. Interestingly, when apoptotic neutrophils are phagocytosed by reticular endothelial macrophages in the spleen and liver or by macrophages on a site of infection, the production of G-CSF is suppressed to limit the inflammation[ 98 ].
This way, via the up regulation of G-CSF production directly in the bone marrow, the production of new neutrophils can be tightly regulated. So if neutrophils are already apoptotic in circulation, the spleen and liver will clear them.
On the other hand, senescent neutrophils can migrate back into the bone marrow and will be cleared there, as a positive feedback loop for neutrophil production.
To determine whether homing neutrophils can return to circulation, isolated neutrophils from the bone marrow and peripheral blood of mice were labeled and injected back into the mice[ 92 ].
About 20 percent of labeled mature bone marrow neutrophils remobilized during an inflammatory response. However, homed bone marrow peripheral neutrophils could not be remobilized in response to inflammation. Therefore, the bone marrow could be seen as a site for clearance.
In addition, this study also showed that infused marrow neutrophils may be remobilized. It would be very interesting to further investigate the recirculating potential of mature neutrophils, as this can greatly influence our understanding of neutrophil kinetics. The kinetics of neutrophil production, the amount of cells that are produced each day, is measured as a rate of turnover of neutrophils in the blood.
Blood neutrophil turnover has been determined by labeling neutrophils with [ 32 P] DFP di-isopropyl fluorophosphate and has been described to be about 1. Marrow neutrophil production has been determined from the number of neutrophils in the post mitotic pool, divided by their transit time the appearance in circulating neutrophils of injected 3 H-thymidine Figure 4. The post mitotic pool consists of about 5.
The marrow neutrophil production has therefore been calculated to be 0. This amount corresponds to the calculated neutrophil turnover in blood. However, when cells were labeled with di-isopropylfluorophosphate- 32 P, a larger turnover of neutrophils was found. Care should thus be taken with calculations and amounts, as they depend on the method to label cells[ 14 ]. The different maturation stages all have different kinetics, which are studied in vivo and in vitro using radioisotopic labeling.
These studies indicate that between the myeloblast and the myelocyte stages, approximately five cell divisions occur[ , ]. Myelocytes probably undergo about three cell divisions, indicating the major expansion of the neutrophil pool to be at the myelocyte stage. These radionuclide studies suggest that the transit time from myeloblast to myelocyte takes about h, divided over the different myelocyte stages Figure 2. The transition from myelocyte to blood neutrophil takes about h, indicating a total time of approximately 12 d from precursor to mature neutrophil[ ].
During infection, transition time from myelocyte to blood neutrophil can be shortened to 48 h. Following production, mature post mitotic neutrophils approximately 10 11 cells will remain in the bone marrow for d[ 14 , ]. In response to infection, the storage pool in the bone marrow will be used as source of neutrophils for blood neutrophilia[ ]. In conclusion, before a neutrophil leaves the bone marrow, it takes 17 d to be produced and maturated[ ].
The kinetics of neutrophils leaving the vascular compartment and their take-over by new neutrophils can easily be measured by labeling neutrophils and measure the transit time through the vascular compartment. When healthy individuals are injected with neutrophils, they leave the vascular compartment with a 7 h half life time[ 17 , ]. Using radiolabelled neutrophils and other analytical techniques, the neutrophil intravascular transit time has been measured for the liver, spleen and bone marrow, being respectively 2 and 10 min.
The intravascular transit time can be seen as the mean time taken for neutrophils to pass through the capillary bed of a specific organ. The influence of the marginated pool, homing back to the bone marrow and the kinetics in the spleen and liver on this transit time is unknown. As the regulation of neutrophil production and clearance is an important homeostatic mechanism and also involved in the development of systemic inflammatory states, it is of great importance that the kinetics of circulation and clearance are clear.
Now we know that not only the liver and spleen, but also the bone marrow clears neutrophils, and that the different organs clear different types of neutrophils[ 92 ]. But the function of neutrophils leaving the vascular compartment is largely unknown. As described before, inflammatory neutrophils were found to have many more functions then only clearance of microbes.
Possibly, neutrophils in marginated sites outside the vascular compartment, also have additional functions. There is growing evidence that to a certain extend neutrophils influence the adaptive immune response, either through pathogen shuttling to the lymph nodes[ ], through antigen presentation[ ], and through modulation of T helper responses[ ]. However, these described functions have still not been shown in vivo and also, are they neutrophil specific or do they occur as side effects of the functioning as a microbe-killer.
Without signs of infection, neutrophils do not get activated and have no need to go into the tissues. They also do not exocytose their granules, meaning that they are not as harmful for the host as activated neutrophils. The fate of these unactivated neutrophils is hard to investigate.
Labeling neutrophils has revealed some of their fate, but labeling can also cause changes in the neutrophil e. However, the studies which labeled neutrophils and followed their route through the human body are still very useful in this context. In studies measuring neutrophil kinetics, different types of radioactive labeling have been used. Furthermore, the label is only slightly or not at all attached to lymphocytes or monocytes[ ].
The effects of these radioactive labels on neutrophils have been studied by several authors, for example the effects on chemotactic responsiveness[ ]. Some labels are no longer in use, for example Na 2 51 CrO 4 and SnCl 2 -reduced 99m TcO 4 - , which showed less optimal results in the chemotactic responsiveness studies. Other labels are still used, for example 32 DFP or 3 H-thymidine. For a long time, only in vitro labeling was possible, where neutrophils were isolated from a blood sample, which could easily stimulate the neutrophils.
Upon stimulation, neutrophils release their granules and are altered in surface receptor expression, and although the labeling experiments have been improved hardly any research was done to assess the activation of neutrophils or the change in surface receptor expression due to labeling[ ]. Some authors claim that there is no difference in neutrophil activation, without showing the data. But as neutrophils are quick responders to differences in their homeostatic environment, in vitro , in vivo or in situ labeling can have tremendous effects on the cell, affecting the outcome of a study as well.
In mice, neutrophils were shown to have a half-life of 8 to 10 h when labeled in vivo [ ]. This shows that the methods for labeling can have an devastating effect on the outcome of the study. But unfortunately, extrapolation of mice experiments is often very difficult.
In mice, neutrophils are not the main circulating white blood cell-type, they do not express the same receptors as human neutrophils for example there is a lack CXCR1 and also chemoattractant CXCL-8 does not exist in mice. Therefore, care should be taken when mice are used for calculating neutrophil life spans. Most experiments done with in vitro labeling have not been repeated with in vivo labeling, meaning that some knowledge needs to be adjusted. Recently, Pillay et al [ 16 ] used 2 H 2 O, a new labeling method for labeling neutrophil pools in vivo , to calculate the rate of division of the mitotic pool in the bone marrow, the transit time of new neutrophils through the post mitotic pool and the delay in mobilization of neutrophils from the post mitotic pool to the blood.
They recalculated the life-span of neutrophils and found an average circulatory neutrophil lifespan of 5. However, there are also doubts concerning this report, as the previously used radioactive labels e. The new model is thought to lack the right temporal resolution to make these conclusions, as the mean value of the total life span of a neutrophil is in line with the previously described total life span[ ].
Also, the authors did not show that the deuterium was not reutilized in newly dividing neutrophil precursor, thereby possibly influencing the results[ 18 ]. Either one of these two numbers should be reconsidered. Interestingly, different maturation states of neutrophils are labeled by different radioactive labels.
Warner and Athens compared the three most common radioactive labels in vitro until , 3 H-thymidine, 32 P-labeled sodium phosphate and 32 DFP, in their kinetics regarding the blood granulocyte radioactivity curves measured after administration[ ].
The component s in the granulocytes to which DFP binds is unknown as DFP binds many different esterases and proteolytic enzymes[ ]. When the blood kinetics of all three populations is compared, they are all three totally different: 32 DFP levels start high, where after the labeled neutrophils disappear in marginated pools and the level of 32 DFP declines.
In our opinion in vivo labeling is the better method. Isolating blood cells, processing and inject them again in the recipient can have dramatic effects on their life span.
When leukemia patients are transfused with donated red blood cells after bone marrow transplantation, the half life on the donated red blood cells is dramatically reduced, leading to massive clearance of red blood cells. The released iron due to this enhanced turnover is a well known complication of red cell transfusion[ ]. This indicates that even careful isolation of blood cells without any labeling has an impressive effect on their life span. A proper understanding of the lifespan and distribution of the neutrophil is very important, as the neutrophil can vary in phenotype and function with a longer lifespan, and the lifespan determines the need for influencing the neutrophil function in inflammatory diseases.
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This article has been cited by other articles in PMC. Abstract Neutrophils also called polymorphonuclear leukocytes, PMNs are the most abundant white blood cells in humans and play a central role in innate host defense. Keywords: constitutive apoptosis, phagocytosis-induced cell death, PCNA, intracellular signaling, gene expression, caspases, Mcl-1, Bax, pathogen, intrinsic pathway, extrinsic pathway, apoptosis differentiation program.
Conserved Apoptosis Machinery and Pathways Apoptosis is a conserved mechanism of programed cell death. Open in a separate window. Figure 1. Caspases Caspases are a family of cysteine proteases with roles in apoptosis, inflammation, and development. The extrinsic pathway Ligation and oligomerization of Fas, TNF receptor 1, or the TRAIL receptor triggers formation of a receptor-associated death-inducing complex for recruitment and activation of caspase The intrinsic pathway The intrinsic pathway is critical for both constitutive and stimulated PMN apoptosis.
Myeloid nuclear differentiation antigen MNDA MNDA is a recently identified regulatory factor that relocalizes from the nucleus to the cytosol in aging PMNs, is cleaved by caspases, and directly associates with Mcl-1 to promote its degradation via the proteasome. The Neutrophil Apoptosis Differentiation Program and PICD Our understanding of the role of gene expression in neutrophil turnover was revolutionized by DeLeo and colleagues, who were the first to demonstrate in an elegant series of studies that constitutive neutrophil apoptosis requires changes in gene expression that collectively comprise an apoptosis differentiation program.
Effects of Pro-survival Signaling on Neutrophil Apoptosis and Lifespan Several partially overlapping signaling pathways associated with activation of phosphatidylinositol 3-kinase PI3K and Akt, ERK, and NFkB act downstream of growth factor receptors, adhesion receptors, and TLR4 to temporarily delay apoptosis as a means to ensure the viability of neutrophils as they migrate from the bloodstream into infected and inflamed tissues.
Manipulation of PMN Apoptosis by Microbial Pathogens In the past few years, our understanding of the ability of bacterial, fungal, parasitic, and viral pathogens to manipulate PMN turnover has increased dramatically. Figure 2. Extending neutrophil lifespan for intracellular growth Anaplasma phagocytophilum is an obligate intracellular pathogen of neutrophils, and a large body of data indicates that this organism uses a multifaceted strategy to modulate multiple apoptotic and survival signaling pathways in PMNs.
Pathogen acceleration of apoptosis and induction of cell lysis Enhanced neutrophil apoptosis in HIV infection is believed to contribute to the elevated risk of secondary infections that are characteristic of AIDS.
Neutrophils as Trojan horses Although it has been known for several years that Leishmania promastigotes infect macrophages, differentiate into amastigotes, and replicate in lysosome-like compartments, recent data suggest that neutrophils may be the first cell type infected.
Neutrophil Apoptosis in Inflammatory Disease Delayed neutrophil apoptosis contributes to the pathology of many inflammatory and autoimmune diseases.
Therapeutic Intervention Recently developed treatments for infections and inflammatory disorders exploit the biology of neutrophil apoptosis to drive resolution of inflammation and minimize tissue damage. Conclusions Recent advances in the understanding of neutrophil biology have shed light on the mechanisms that control cell death and survival under homeostatic conditions as well as during infection and inflammation.
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