Phagocytes are key effector immune cells responsible for various biological processes; from orchestrating responses against invading pathogens to maintaining tissue homeostasis and neutrophils are the most abundant population of granulocytic phagocytes present in mammalian blood (Adrover et al., 2019; Hidalgo et al., 2019; Ng et al., 2019; Yvan-Charvet and Ng, 2019; Evrard et al., 2018). Neutrophil and heterophils (a functionally analogous granulocytic phagocyte population present in non-mammals and some mammals; Montali, 1988) arise from a shared pool of haematopoietic stem cells and mitotic myeloid progenitor cells that can also differentiate into monocytes, eosinophils and basophils following exposure to the relevant growth factor (Adrover et al., 2019; Yvan-Charvet and Ng, 2019; Mehta et al., 2014). The development and life cycle of mammalian neutrophils through a continuum of multipotent progenitors to a post-mitotic mature cell has been well described and has been recently reviewed (Hidalgo et al., 2019; Yvan-Charvet and Ng, 2019).

The development and function of myeloid phagocytes is mediated through lineage-specific transcription factors and pleiotropic glycoproteins - termed colony-stimulating factors (CSFs)- acting in concert on myeloid progenitor cells. CSF1, CSF3, and their cognate receptors, are lineage-specific and responsible for the differentiation and function of monocytes/macrophages and neutrophils, respectively (for full nomenclature see Supplementary file 1; Dai et al., 2002; Yoshida et al., 1990; Umeda et al., 1996; Liu et al., 1996; Lieschke et al., 1994). There is a large body of evidence demonstrating the requirement of CSFs for cell development as multiple studies in knockout mice have shown that CSF1R/CSF1 and CSF3R/CSF3 are linked to the development of monocytes and neutrophils in vivo. The loss of CSF3 or CSF3R directly affects neutrophil populations resulting in a severe neutropenia, but not the complete loss of mature neutrophils in the models studied (Liu et al., 1996; Lieschke et al., 1994; Basu et al., 2000). The loss of CSF1 caused reduced cavity development of the bone marrow, loss of some progenitor populations, monocytopenia, and a reduced population of neutrophils in the bone marrow, although interestingly, elevated levels of neutrophils were observed in the periphery (Dai et al., 2002; Yoshida et al., 1990; Hibbs et al., 2007).

Similarly, in humans, single gene mutations have been described in both CSF3 and CSF3R resulting in severe congenital neutropenia (SCN). Furthermore, mutations in ELANE, a gene that encodes for the neutrophil granule serine protease -neutrophil elastase- and acts as a negative regulator of CSF3R signalling can also result in SCN (Piper et al., 2010; Hunter et al., 2003; Garg, 2020; Nayak et al., 2015). In contrast to some animal models, individuals present as children with early onset life-threatening infections because they lack mature neutrophils in the circulation as the neutrophil progenitors in the bone marrow do not progress beyond the myelocyte/promyelocyte stage (Lakshman and Finn, 2001). These studies demonstrate that CSF receptor/ligand pairings are essential for homeostatic neutrophil development and are intrinsically linked with neutrophil function, arguably making them ideal surrogates to study neutrophil evolution. Through multiple methods we examined the emergence of the respective CSF ligand and receptor genes and proteins across the Chordate phylum and demonstrated how CSF1R/CSF1 and CSF3R/CSF3 pairings contributed to the evolutionary adaptations of the mammalian neutrophil.

The mammalian neutrophil is a highly specialised cell that acts as a first responder to insults against a host immune system as well as acting in an equally important sentinel role (Hidalgo et al., 2019; Ng et al., 2019). They are functionally conserved across phylum Chordata and constitute the largest population of myeloid cells in the blood of birds and mammals. In humans, for example, up to one billion neutrophils per kilogram of body weight are produced in the bone marrow each day (Yvan-Charvet and Ng, 2019). The immune response has evolved in such a way as to be able to respond efficiently to a variety of threats, and it is interesting that a resource such as the bone marrow should be expended on the production and maintenance of the relatively short-lived neutrophil at the expense of the eosinophil and basophil. The timescale modelling demonstrates that prior to the advent of tetrapoda lineages, the neutrophil was in a pool of different WBC populations at the disposal of the jawed/jawless fish. However, the appearance of CSF3, altered the distribution and with each emerging animal order, a different granulocyte was favoured, presumably, for cell-specific adaptations in response to environmental challenges. Thus, suggesting that CSFR1R/CSF1 and CSF3R/CSF3 signalling conferred adaptations on the neutrophil that proved evolutionarily advantageous. The work discussed here focusses on the mammalian neutrophil within the context of blood, further work is required to define similar aspects as regards to other tissue resident populations such as macrophages or granulocytes.

The bone marrow is an essential site for granulopoiesis and myelopoiesis. As multipotent haematopoietic stem cells (HSCs) progress through different vascular niches within the bone marrow they sequentially lose their potential to form other lineages in response to environmental cues from bone marrow dwelling macrophages and stromal endothelial cells (Ng et al., 2019; Yvan-Charvet and Ng, 2019; Greenbaum and Link, 2011). The emergence of CSF1 in tetrapod lineages likely led to the appearance of bone and bone marrow. A consequence of this was the gradual re-organisation of haematopoiesis away from existing haematopoietic tissues, such as the eosinophil rich Leydig organ of sharks to tissue-specific compartments in the bone marrow. CSF1, in conjunction with another factor, receptor activator of nuclear factor-κB ligand (RANKL), co-ordinate the reabsorption of old bone through haematopoietically derived osteoclasts to allow the generation of new bone. CSF1 and RANKL (which emerged at a similar point in evolution) orchestrate bone-remodelling through their respective receptors, CSF1R and RANK (Kim and Kim, 2016). This suggests that by the time a bone structure had evolved in amphibia, the bone marrow had become the principle site of haematopoiesis, although there are some exceptions within various anurans (de Abreu Manso et al., 2009).

In contrast to peripheral blood, CSF3 is expressed on a number of cells in the bone marrow including; neutrophils, monocytes, B cells, myeloid progenitors and HSCs (Greenbaum and Link, 2011; Petit et al., 2002; Semerad et al., 2005; Lévesque et al., 2003). Although CSF3 can likely act directly on HSCs through their receptor, it is believed to indirectly mobilise HSCs through a monocytic intermediary that secretes CSF3, which leads to suppression of the CXCR4:CXCL12 axis, alteration of the bone marrow niche, and the subsequent release of HSCs (Greenbaum and Link, 2011; Petit et al., 2002; Semerad et al., 2005; Lévesque et al., 2003). In a similar process, CSF3 can suppress B cell lymphopoiesis by again targeting CXCL12 and suppressing other B cell tropic factors or stromal cells that favour the lymphoid niche (Day et al., 2015). Thus, the emergence of CSF3R/CSF3 conferred the adaptation, or advantage, of control of the biological machinery i.e. CSF3 provides a mechanism through which haematopoiesis can be shaped and deployed in favour of maximal neutrophil generation. This broadly aligns with the neutrophil starting to dominate peripheral populations in the transition from amphibia to the lizards of early squamata following the appearance of bone.

Mammalian neutrophil production occurs in the haematopoietic cords present within the venous sinuses and the daily output is approximately 1.7 × 10⁹/kg (Summers et al., 2010). As our data demonstrate high levels of neutrophil output are common across warm-blooded chordates and neutrophil/heterophils are the predominant granulocyte in birds and mammals, in what could be considered an example of convergent evolution. One of the fundamental requirements of the host innate immune response is to be able to respond rapidly to perceived threats that can be present at any site in the body, which requires the cellular arm to be constantly present and available. Theoretically this can be achieved in the steady state by having either low volumes of long-lived cells or high volumes of short-lived cells circulating in the periphery. As a consequence, there are potential biological trade-offs when considering each setting, firstly; the longer a cell survives in the periphery, the more effort is required by the host to maintain its survival in terms of providing appropriate cues and growth factors. Secondly, while a short-lived cell does not need as much host input for survival, a high turnover is required in order to ensure it doesn’t compete for growth factors with other cell types or cause damage by being retained beyond its usefulness. The latter setting fits with the observed neutrophil life cycle and could be considered an evolutionary adaptation. The CSF3R/CSF3 signalling pathway is essential for generating high neutrophil numbers without adverse effects to the host.

The neutrophil has a short circulatory half-life in the steady state of approximately one day (Ng et al., 2019; Yvan-Charvet and Ng, 2019), although this does remain controversial as some estimates of the circulatory lifespan are as much as five days (Pillay et al., 2010). By contrast, a mature eosinophil has a short circulatory lifespan of approximately 18 hr before relocating to the tissue, where it will survive for a further 2–5 days (Park and Bochner, 2010). Similarly, intermediate and non-classical monocytes can survive in the periphery for four and seven days respectively (Patel et al., 2017). In human studies, CSF3 has been shown to ‘effectively’ shorten the lifespan of neutrophil myeloblasts and promyelocytes by decreasing their time spent in cell cycle and accelerating their progress to maturation (Lord et al., 1989). Although, it is unclear what the exact effect is on the lifespan of post-mitotic neutrophils, studies have shown that the addition of exogenous CSF3 can delay apoptosis in mature neutrophils (van Raam et al., 2008; Zimbelman et al., 2002). This suggests that under certain conditions; such as infection, CSF3 can extend the lifespan of a mature neutrophil. Interestingly, classical monocytes also express CSF3R and have a short circulating lifespan of approximately 24 hr (Patel et al., 2017) These studies suggest that under steady state conditions and below a certain threshold, CSF3 has an as-yet-undocumented role either directly or indirectly in maintaining a short neutrophil lifespan and thus allowing the efficient turnover required to sustain high levels of granulopoiesis.

CSF3 orchestrates the life cycle of neutrophils in the bone marrow microenvironment by marshalling neutrophil progenitors through different development stages through to maturity, which is indicative of the inductive model of differentiation (Stanley, 2009). Accordingly, in response to this, CSF3R is expressed though every life stage, although at differing levels across the neutrophil populations, with the highest levels observed on mature cells where it is expressed at between two and three-fold more than on progenitors (Demetri and Griffin, 1991). CSF3R/CSF3 signalling has a dual role in controlling the distribution of neutrophils by both retaining a population of mature neutrophils in the bone marrow as a reservoir and facilitating the egress of other neutrophils into the periphery. Thus, a major evolutionary adaptation that CSF3R/CSF3 has conferred to the neutrophil is the ability to move, both on a population-wide and individual cell level.

There is abundant production of neutrophils daily in the bone marrow; however, there are far fewer neutrophils in circulation in the blood than are produced during granulopoiesis as the total neutrophil population is effectively stored in the bone marrow or marginated in intravascular pools within the spleen and liver (Ussov et al., 1995). Neutrophils can transit between sites in response to CSF3 signalling and it is estimated that 49% of cells are present in the circulating pool and the remaining 51% are marginated in discrete vascular pools (Summers et al., 2010; Athens et al., 1961). In the event of an infection, neutrophils can be mobilised from the marginated pools and bone marrow in response to CSF3-induced production of mobilising signals such as CXCL1 (Köhler et al., 2011). The co-ordinated egress of neutrophils from the bone marrow is achieved by CSF3 interacting with the CXCR4/CXCL12 and CXCR2/CXCL2 signalling pathways. CSF3 disrupts the CXCR4-CXCL12 retention axis by reducing CXCL12 release from endothelial stromal cells and reducing CXCR4 expression on neutrophils, thus allowing the movement of mature neutrophils through the venous sinuses to the periphery. CSF3-induced expression of CXCR2 on neutrophils then causes their migration to the vasculature along a CXCL2 chemotactic gradient (Adrover et al., 2019; Eash et al., 2010; Eash et al., 2009).

As neutrophils enter the bloodstream, they need to be able to migrate easily around the circulatory system under high flow conditions. This requires the neutrophil’s physical form to have high deformability and flexibility as it encounters the different diameters of the vasculature. The neutrophil nucleus is functionally adapted to this role because of its multi-nucleated structure and the distinct protein composition of the nuclear envelope, features that are widely conserved across mammalian species (Manley et al., 2018). CSF3 in co-ordination with C/EBPε and the ETS factors; Pu.1 and GA-binding protein (GABP) are responsible for the transcriptional control of the essential neutrophil nuclear structural proteins; Lamin A, Lamin C and Lamin B receptor (LBR) (Malu et al., 2016; Cohen et al., 2008). In comparison to other cell nuclear protein compositions, neutrophils have a low proportion of Lamin A and Lamin C, which is believed to make the nucleus more flexible for easier transit (Manley et al., 2018; Malu et al., 2016; Cohen et al., 2008). In contrast, the levels of LBR are increased, which is required for nuclear lobulation and subsequent neutrophil maturation (Manley et al., 2018; Malu et al., 2016). However, recent work has also demonstrated that band cells (immature neutrophils) are capable of just as efficient migration with incomplete nuclear segmentation as mature neutrophils (van Grinsven et al., 2019). Taken together, these factors support the argument that CSF3 signalling and C/EBPε are intrinsic to the evolution of mammalian neutrophil cell motility.

The evolution of CSF3R/CSF3 has been essential to the development of the neutrophil/heterophil in chordates and its own existence as the principle neutrophil growth factor is evolutionarily advantageous. Some members of the jawed/jawless lineages are unique in that they have populations of both neutrophils and heterophils, whereas later linages favour either neutrophils or heterophils. Our analysis shows that CSF3R/CSF3 emerged before the advent of jawed/jawless fish as both are present in the Coelacanth and absent from the other lineages. Intriguingly, an IL6-like gene was present in the same syntenic location of the whale shark, suggesting the possibility that heterophils and neutrophils were independently controlled by an IL6-like protein and CSF3 in the early lineages. IL6 is an important pleiotropic pro-inflammatory cytokine that plays key roles in infection, inflammation and haematopoiesis (Tanaka et al., 2014). Although CSF3R and IIL6R, which are functional paralogues, diverged from each other many millions of years ago, there is still functional redundancy at the cell level in modern-day mammals, as neutrophils are present - though at vastly reduced numbers - in CSF3^-/- and CSF3R^-/- mice (Liu et al., 1996; Lieschke et al., 1994). IL-6 can act on neutrophil progenitors and immature neutrophils thus supporting neutrophil development in the bone marrow of CSF3-deficient mice (Basu et al., 2000). However, mature neutrophils are refractory to IL-6 signalling as the expression of the IL-6R subunit gp130 is lost during maturation (Wilkinson et al., 2018). From amphibia onwards, the protein analysis here suggests that CSF3R and CSF3 co-evolved closely together and in contrast to CSF1R/CSF1/IL34, CSF3 is likely the only ligand of CSF3R.

Using various in-silico approaches, these findings have demonstrated how essential CSF3R and CSF3 (and to a lesser extent CSF1R and CSF1) are to the predominance of mammalian neutrophils in blood. Through the course of evolution, CSF3R/CSF3 signalling has accrued many properties that are responsible for the survival of the neutrophil and its ability to function, such as cell motility and mobility. Interestingly, although CSF3 is present in jawed/jawless fish lineages, it’s not until the emergence of tetrapoda that CSF3R and CSF3 begin to dominate haematopoiesis. Our current studies have been limited to chordates in which the data is publicly available and as the datasets continue to be expanded and updated, our hypothesis may need to change to reflect that. However, we would argue that this approach is a valid method for exploring the origins of the neutrophil granulocyte and would further be supported by the physical isolation and characterisation of neutrophils, associated genes and proteins in the different animal orders within Phylum Chordata.

We also envisage exploring the phagocytic granulocyte of two model species. The amphioxus is considered the basal chordate and a macrophage-like population has been identified, although a neutrophil/heterophil has yet to be described within the rudimentary circulatory system (Han et al., 2010). The lungfish, a primitive airbreathing fish, is unique among jawed/jawless lineages as it lives in freshwater and can survive on the land for up to one year. Accordingly, the lungfish has many adaptations and is considered to be a one of the closest living relatives to tetrapods making it a good model species for further study (Takezaki and Nishihara, 2017). Given how essential motility and mobility are to neutrophil function and development, it would be useful to discern when it emerged in evolution by identifying if equivalent cells and functional gene/protein orthologues are present in either species. These comparative studies would answer fundamental questions about the origin of the neutrophilic phagocyte.

All data generated or analysed during this study are included in the manuscript and supporting files.

1. 1. Adrover JM
   2. Del Fresno C
   3. Crainiciuc G
   4. Cuartero MI
   5. Casanova-Acebes M
   6. Weiss LA
   7. Huerga-Encabo H
   8. Silvestre-Roig C
   9. Rossaint J
   10. Cossío I
   11. Lechuga-Vieco AV
   12. García-Prieto J
   13. Gómez-Parrizas M
   14. Quintana JA
   15. Ballesteros I
   16. Martin-Salamanca S
   17. Aroca-Crevillen A
   18. Chong SZ
   19. Evrard M
   20. Balabanian K
   21. López J
   22. Bidzhekov K
   23. Bachelerie F
   24. Abad-Santos F
   25. Muñoz-Calleja C
   26. Zarbock A
   27. Soehnlein O
   28. Weber C
   29. Ng LG
   30. Lopez-Rodriguez C
   31. Sancho D
   32. Moro MA
   33. Ibáñez B
   34. Hidalgo A

   (2019) A neutrophil timer coordinates immune defense and vascular protection

   Immunity 51:966–967.

   https://doi.org/10.1016/j.immuni.2019.11.001

   • PubMed
   • Google Scholar
2. 1. Akagi T
   2. Thoennissen NH
   3. George A
   4. Crooks G
   5. Song JH
   6. Okamoto R
   7. Nowak D
   8. Gombart AF
   9. Koeffler HP

   (2010) In vivo deficiency of both C/EBPβ and C/EBPε results in highly defective myeloid differentiation and lack of cytokine response

   PLOS ONE 5:e15419.

   https://doi.org/10.1371/journal.pone.0015419

   • PubMed
   • Google Scholar
3. 1. Athens JW
   2. Haab OP
   3. Raab SO
   4. Mauer AM
   5. Ashenbrucker H
   6. Cartwright GE
   7. Wintrobe MM

   (1961) Leukokinetic studies. IV. the total blood, circulating and marginal granulocyte pools and the granulocyte turnover rate in normal subjects

   Journal of Clinical Investigation 40:989–995.

   https://doi.org/10.1172/JCI104338

   • PubMed
   • Google Scholar
4. 1. Basu S
   2. Hodgson G
   3. Zhang H-H
   4. Katz M
   5. Quilici C
   6. Dunn AR

   (2000) “Emergency” granulopoiesis in G-CSF–deficient mice in response to Candida albicans infection

   Blood 95:3725–3733.

   https://doi.org/10.1182/blood.V95.12.3725

   • Google Scholar
5. 1. Benson DA
   2. Karsch-Mizrachi I
   3. Lipman DJ
   4. Ostell J
   5. Sayers EW

   (2009) GenBank

   Nucleic Acids Research 37:D26–D31.

   https://doi.org/10.1093/nar/gkn723

   • PubMed
   • Google Scholar
6. 1. Borregaard N
   2. Cowland JB

   (1997) Granules of the human neutrophilic polymorphonuclear leukocyte

   Blood 89:3503–3521.

   https://doi.org/10.1182/blood.V89.10.3503

   • PubMed
   • Google Scholar
7. 1. Chih DY
   2. Chumakov AM
   3. Park DJ
   4. Silla AG
   5. Koeffler HP

   (1997) Modulation of mRNA expression of a novel human myeloid-selective CCAAT/enhancer binding protein gene (C/EBP epsilon)

   Blood 90:2987–2994.

   https://doi.org/10.1182/blood.V90.8.2987

   • PubMed
   • Google Scholar
8. 1. Cohen TV
   2. Klarmann KD
   3. Sakchaisri K
   4. Cooper JP
   5. Kuhns D
   6. Anver M
   7. Johnson PF
   8. Williams SC
   9. Keller JR
   10. Stewart CL

   (2008) The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils

   Human Molecular Genetics 17:2921–2933.

   https://doi.org/10.1093/hmg/ddn191

   • PubMed
   • Google Scholar
9. 1. Dai XM
   2. Ryan GR
   3. Hapel AJ
   4. Dominguez MG
   5. Russell RG
   6. Kapp S
   7. Sylvestre V
   8. Stanley ER

   (2002) Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in Osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects

   Blood 99:111–120.

   https://doi.org/10.1182/blood.V99.1.111

   • PubMed
   • Google Scholar
10. 1. Day RB
    2. Bhattacharya D
    3. Nagasawa T
    4. Link DC

    (2015) Granulocyte colony-stimulating factor reprograms bone marrow stromal cells to actively suppress B lymphopoiesis in mice

    Blood 125:3114–3117.

    https://doi.org/10.1182/blood-2015-02-629444

    • PubMed
    • Google Scholar
11. 1. de Abreu Manso PP
    2. de Brito-Gitirana L
    3. Pelajo-Machado M

    (2009) Localization of hematopoietic cells in the bullfrog (Lithobates catesbeianus)

    Cell and Tissue Research 337:301–312.

    https://doi.org/10.1007/s00441-009-0803-0

    • PubMed
    • Google Scholar
12. 1. Demetri GD
    2. Griffin JD

    (1991) Granulocyte colony-stimulating factor and its receptor

    Blood 78:2791–2808.

    https://doi.org/10.1182/blood.V78.11.2791.bloodjournal78112791

    • PubMed
    • Google Scholar
13. 1. Eash KJ
    2. Means JM
    3. White DW
    4. Link DC

    (2009) CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions

    Blood 113:4711–4719.

    https://doi.org/10.1182/blood-2008-09-177287

    • Google Scholar
14. 1. Eash KJ
    2. Greenbaum AM
    3. Gopalan PK
    4. Link DC

    (2010) CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow

    Journal of Clinical Investigation 120:2423–2431.

    https://doi.org/10.1172/JCI41649

    • PubMed
    • Google Scholar
15. 1. Engström PG
    2. Ho Sui SJ
    3. Drivenes O
    4. Becker TS
    5. Lenhard B

    (2007) Genomic regulatory blocks underlie extensive microsynteny conservation in insects

    Genome Research 17:1898–1908.

    https://doi.org/10.1101/gr.6669607

    • PubMed
    • Google Scholar
16. 1. Evrard M
    2. Kwok IWH
    3. Chong SZ
    4. Teng KWW
    5. Becht E
    6. Chen J
    7. Sieow JL
    8. Penny HL
    9. Ching GC
    10. Devi S
    11. Adrover JM
    12. Li JLY
    13. Liong KH
    14. Tan L
    15. Poon Z
    16. Foo S
    17. Chua JW
    18. Su IH
    19. Balabanian K
    20. Bachelerie F
    21. Biswas SK
    22. Larbi A
    23. Hwang WYK
    24. Madan V
    25. Koeffler HP
    26. Wong SC
    27. Newell EW
    28. Hidalgo A
    29. Ginhoux F
    30. Ng LG

    (2018) Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions

    Immunity 48:364–379.

    https://doi.org/10.1016/j.immuni.2018.02.002

    • PubMed
    • Google Scholar
17. 1. Forslund K
    2. Pekkari I
    3. Sonnhammer EL

    (2011) Domain architecture conservation in orthologs

    BMC Bioinformatics 12:326.

    https://doi.org/10.1186/1471-2105-12-326

    • PubMed
    • Google Scholar
18. 1. Garg B

    (2020) Inducible expression of a disease-associated

    The Journal of Biological Chemistry 295:7492–7500.

    https://doi.org/10.1074/jbc.RA120.012366

    • Google Scholar
19. 1. Genovese KJ
    2. He H
    3. Swaggerty CL
    4. Kogut MH

    (2013) The avian heterophil

    Developmental & Comparative Immunology 41:334–340.

    https://doi.org/10.1016/j.dci.2013.03.021

    • PubMed
    • Google Scholar
20. 1. Glasauer SM
    2. Neuhauss SC

    (2014) Whole-genome duplication in teleost fishes and its evolutionary consequences

    Molecular Genetics and Genomics 289:1045–1060.

    https://doi.org/10.1007/s00438-014-0889-2

    • PubMed
    • Google Scholar
21. 1. Greenbaum AM
    2. Link DC

    (2011) Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization

    Leukemia 25:211–217.

    https://doi.org/10.1038/leu.2010.248

    • PubMed
    • Google Scholar
22. 1. Halene S
    2. Gaines P
    3. Sun H
    4. Zibello T
    5. Lin S
    6. Khanna-Gupta A
    7. Williams SC
    8. Perkins A
    9. Krause D
    10. Berliner N

    (2010) C/EBPepsilon directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via hlx

    Experimental Hematology 38:90–103.

    https://doi.org/10.1016/j.exphem.2009.11.004

    • PubMed
    • Google Scholar
23. 1. Han Y
    2. Huang G
    3. Zhang Q
    4. Yuan S
    5. Liu J
    6. Zheng T
    7. Fan L
    8. Chen S
    9. Xu A

    (2010) The primitive immune system of amphioxus provides insights into the ancestral structure of the vertebrate immune system

    Developmental & Comparative Immunology 34:791–796.

    https://doi.org/10.1016/j.dci.2010.03.009

    • PubMed
    • Google Scholar
24. 1. Hatano Y
    2. Taniuchi S
    3. Masuda M
    4. Tsuji S
    5. Ito T
    6. Hasui M
    7. Kobayashi Y
    8. Kaneko K

    (2009) Phagocytosis of heat-killed Staphylococcus aureus by eosinophils: comparison with neutrophils

    Apmis 117:115–123.

    https://doi.org/10.1111/j.1600-0463.2008.00022.x

    • PubMed
    • Google Scholar
25. 1. Hibbs ML
    2. Quilici C
    3. Kountouri N
    4. Seymour JF
    5. Armes JE
    6. Burgess AW
    7. Dunn AR

    (2007) Mice lacking three myeloid colony-stimulating factors (G-CSF, GM-CSF, and M-CSF) still produce macrophages and granulocytes and mount an inflammatory response in a sterile model of peritonitis

    The Journal of Immunology 178:6435–6443.

    https://doi.org/10.4049/jimmunol.178.10.6435

    • PubMed
    • Google Scholar
26. 1. Hidalgo A
    2. Chilvers ER
    3. Summers C
    4. Koenderman L

    (2019) The neutrophil life cycle

    Trends in Immunology 40:584–597.

    https://doi.org/10.1016/j.it.2019.04.013

    • PubMed
    • Google Scholar
27. 1. Hirai H
    2. Zhang P
    3. Dayaram T
    4. Hetherington CJ
    5. Mizuno S
    6. Imanishi J
    7. Akashi K
    8. Tenen DG

    (2006) C/EBPbeta is required for 'emergency' granulopoiesis

    Nature Immunology 7:732–739.

    https://doi.org/10.1038/ni1354

    • PubMed
    • Google Scholar
28. 1. Hunter MG
    2. Druhan LJ
    3. Massullo PR
    4. Avalos BR

    (2003) Proteolytic cleavage of granulocyte colony-stimulating factor and its receptor by neutrophil elastase induces growth inhibition and decreased cell surface expression of the granulocyte colony-stimulating factor receptor

    American Journal of Hematology 74:149–155.

    https://doi.org/10.1002/ajh.10434

    • PubMed
    • Google Scholar
29. 1. Jones LC
    2. Lin ML
    3. Chen SS
    4. Krug U
    5. Hofmann WK
    6. Lee S
    7. Lee YH
    8. Koeffler HP

    (2002) Expression of C/EBPbeta from the C/ebpalpha gene locus is sufficient for normal hematopoiesis in vivo

    Blood 99:2032–2036.

    https://doi.org/10.1182/blood.V99.6.2032

    • PubMed
    • Google Scholar
30. 1. Kim JH
    2. Kim N

    (2016) Signaling pathways in osteoclast differentiation

    Chonnam Medical Journal 52:12–17.

    https://doi.org/10.4068/cmj.2016.52.1.12

    • PubMed
    • Google Scholar
31. 1. Köhler A
    2. De Filippo K
    3. Hasenberg M
    4. van den Brandt C
    5. Nye E
    6. Hosking MP
    7. Lane TE
    8. Männ L
    9. Ransohoff RM
    10. Hauser AE
    11. Winter O
    12. Schraven B
    13. Geiger H
    14. Hogg N
    15. Gunzer M

    (2011) G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

    Blood 117:4349–4357.

    https://doi.org/10.1182/blood-2010-09-308387

    • PubMed
    • Google Scholar
32. 1. Kovács I
    2. Horváth M
    3. Kovács T
    4. Somogyi K
    5. Tretter L
    6. Geiszt M
    7. Petheő GL

    (2014) Comparison of proton channel, phagocyte oxidase, and respiratory burst levels between human eosinophil and neutrophil granulocytes

    Free Radical Research 48:1190–1199.

    https://doi.org/10.3109/10715762.2014.938234

    • PubMed
    • Google Scholar
33. 1. Lakshman R
    2. Finn A

    (2001) Neutrophil disorders and their management

    Journal of Clinical Pathology 54:7–19.

    https://doi.org/10.1136/jcp.54.1.7

    • PubMed
    • Google Scholar
34. 1. Lekstrom-Himes J
    2. Xanthopoulos KG

    (1999) CCAAT/enhancer binding protein epsilon is critical for effective neutrophil-mediated response to inflammatory challenge

    Blood 93:3096–3105.

    https://doi.org/10.1182/blood.V93.9.3096

    • PubMed
    • Google Scholar
35. 1. Letunic I
    2. Bork P

    (2019) Interactive tree of life (iTOL) v4: recent updates and new developments

    Nucleic Acids Research 47:W256–W259.

    https://doi.org/10.1093/nar/gkz239

    • PubMed
    • Google Scholar
36. 1. Lévesque JP
    2. Hendy J
    3. Takamatsu Y
    4. Simmons PJ
    5. Bendall LJ

    (2003) Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide

    Journal of Clinical Investigation 111:187–196.

    https://doi.org/10.1172/JCI15994

    • PubMed
    • Google Scholar
37. 1. Lieschke GJ
    2. Grail D
    3. Hodgson G
    4. Metcalf D
    5. Stanley E
    6. Cheers C
    7. Fowler KJ
    8. Basu S
    9. Zhan YF
    10. Dunn AR

    (1994) Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization

    Blood 84:1737–1746.

    https://doi.org/10.1182/blood.V84.6.1737.1737

    • PubMed
    • Google Scholar
38. 1. Liu F
    2. Wu HY
    3. Wesselschmidt R
    4. Kornaga T
    5. Link DC

    (1996) Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice

    Immunity 5:491–501.

    https://doi.org/10.1016/S1074-7613(00)80504-X

    • PubMed
    • Google Scholar
39. 1. Lord BI
    2. Bronchud MH
    3. Owens S
    4. Chang J
    5. Howell A
    6. Souza L
    7. Dexter TM

    (1989) The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo

    PNAS 86:9499–9503.

    https://doi.org/10.1073/pnas.86.23.9499

    • PubMed
    • Google Scholar
40. 1. Malu K
    2. Garhwal R
    3. Pelletier MGH
    4. Gotur D
    5. Halene S
    6. Zwerger M
    7. Yang Z-F
    8. Rosmarin AG
    9. Gaines P

    (2016) Cooperative Activity of GABP with PU.1 or C/EBPε Regulates Lamin B Receptor Gene Expression, Implicating Their Roles in Granulocyte Nuclear Maturation

    The Journal of Immunology 197:910–922.

    https://doi.org/10.4049/jimmunol.1402285

    • Google Scholar
41. 1. Manley HR
    2. Keightley MC
    3. Lieschke GJ

    (2018) The neutrophil nucleus: an important influence on neutrophil migration and function

    Frontiers in Immunology 9:2867.

    https://doi.org/10.3389/fimmu.2018.02867

    • PubMed
    • Google Scholar
42. 1. Mehta HM
    2. Glaubach T
    3. Corey SJ

    (2014) Systems approach to phagocyte production and activation: neutrophils and monocytes

    Advances in Experimental Medicine and Biology 844:99–113.

    https://doi.org/10.1007/978-1-4939-2095-2_6

    • PubMed
    • Google Scholar
43. 1. Montali RJ

    (1988) Comparative pathology of inflammation in the higher vertebrates (reptiles, birds and mammals)

    Journal of Comparative Pathology 99:1–26.

    https://doi.org/10.1016/0021-9975(88)90101-6

    • PubMed
    • Google Scholar
44. 1. Morosetti R
    2. Park DJ
    3. Chumakov AM
    4. Grillier I
    5. Shiohara M
    6. Gombart AF
    7. Nakamaki T
    8. Weinberg K
    9. Koeffler HP

    (1997) A novel, myeloid transcription factor, C/EBP epsilon, is upregulated during granulocytic, but not monocytic, differentiation

    Blood 90:2591–2600.

    https://doi.org/10.1182/blood.V90.7.2591

    • PubMed
    • Google Scholar
45. 1. Nandi S
    2. Cioce M
    3. Yeung Y-G
    4. Nieves E
    5. Tesfa L
    6. Lin H
    7. Hsu AW
    8. Halenbeck R
    9. Cheng H-Y
    10. Gokhan S
    11. Mehler MF
    12. Stanley ER

    (2013) Receptor-type Protein-tyrosine Phosphatase ζ Is a Functional Receptor for Interleukin-34

    Journal of Biological Chemistry 288:21972–21986.

    https://doi.org/10.1074/jbc.M112.442731

    • Google Scholar
46. 1. Nayak RC
    2. Trump LR
    3. Aronow BJ
    4. Myers K
    5. Mehta P
    6. Kalfa T
    7. Wellendorf AM
    8. Valencia CA
    9. Paddison PJ
    10. Horwitz MS
    11. Grimes HL
    12. Lutzko C
    13. Cancelas JA

    (2015) Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells

    Journal of Clinical Investigation 125:3103–3116.

    https://doi.org/10.1172/JCI80924

    • PubMed
    • Google Scholar
47. 1. Ng LG
    2. Ostuni R
    3. Hidalgo A

    (2019) Heterogeneity of neutrophils

    Nature Reviews. Immunology 19:255–265.

    https://doi.org/10.1038/s41577-019-0141-8

    • PubMed
    • Google Scholar
48. 1. Park YM
    2. Bochner BS

    (2010) Eosinophil survival and apoptosis in health and disease

    Allergy, Asthma and Immunology Research 2:87–101.

    https://doi.org/10.4168/aair.2010.2.2.87

    • Google Scholar
49. 1. Patel AA
    2. Zhang Y
    3. Fullerton JN
    4. Boelen L
    5. Rongvaux A
    6. Maini AA
    7. Bigley V
    8. Flavell RA
    9. Gilroy DW
    10. Asquith B
    11. Macallan D
    12. Yona S

    (2017) The fate and lifespan of human monocyte subsets in steady state and systemic inflammation

    Journal of Experimental Medicine 214:1913–1923.

    https://doi.org/10.1084/jem.20170355

    • PubMed
    • Google Scholar
50. 1. Petit I
    2. Szyper-Kravitz M
    3. Nagler A
    4. Lahav M
    5. Peled A
    6. Habler L
    7. Ponomaryov T
    8. Taichman RS
    9. Arenzana-Seisdedos F
    10. Fujii N
    11. Sandbank J
    12. Zipori D
    13. Lapidot T

    (2002) G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4

    Nature Immunology 3:687–694.

    https://doi.org/10.1038/ni813

    • PubMed
    • Google Scholar
51. 1. Pillay J
    2. den Braber I
    3. Vrisekoop N
    4. Kwast LM
    5. de Boer RJ
    6. Borghans JA
    7. Tesselaar K
    8. Koenderman L

    (2010) In vivo labeling with 2h2o reveals a human neutrophil lifespan of 5.4 days

    Blood 116:625–627.

    https://doi.org/10.1182/blood-2010-01-259028

    • PubMed
    • Google Scholar
52. 1. Piper MG
    2. Massullo PR
    3. Loveland M
    4. Druhan LJ
    5. Kindwall-Keller TL
    6. Ai J
    7. Copelan A
    8. Avalos BR

    (2010) Neutrophil elastase downmodulates native G-CSFR expression and granulocyte-macrophage colony formation

    Journal of Inflammation 7:5.

    https://doi.org/10.1186/1476-9255-7-5

    • Google Scholar
53. 1. Pruitt KD
    2. Tatusova T
    3. Maglott DR

    (2007) NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins

    Nucleic Acids Research 35:D61–D65.

    https://doi.org/10.1093/nar/gkl842

    • PubMed
    • Google Scholar
54. 1. Sayers EW
    2. Barrett T
    3. Benson DA
    4. Bryant SH
    5. Canese K
    6. Chetvernin V
    7. Church DM
    8. DiCuccio M
    9. Edgar R
    10. Federhen S
    11. Feolo M
    12. Geer LY
    13. Helmberg W
    14. Kapustin Y
    15. Landsman D
    16. Lipman DJ
    17. Madden TL
    18. Maglott DR
    19. Miller V
    20. Mizrachi I
    21. Ostell J
    22. Pruitt KD
    23. Schuler GD
    24. Sequeira E
    25. Sherry ST
    26. Shumway M
    27. Sirotkin K
    28. Souvorov A
    29. Starchenko G
    30. Tatusova TA
    31. Wagner L
    32. Yaschenko E
    33. Ye J

    (2009) Database resources of the national center for biotechnology information

    Nucleic Acids Research 37:D5–D15.

    https://doi.org/10.1093/nar/gkn741

    • PubMed
    • Google Scholar
55. 1. Scott LM
    2. Civin CI
    3. Rorth P
    4. Friedman AD

    (1992) A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells

    Blood 80:1725–1735.

    https://doi.org/10.1182/blood.V80.7.1725.1725

    • Google Scholar
56. 1. Screpanti I
    2. Romani L
    3. Musiani P
    4. Modesti A
    5. Fattori E
    6. Lazzaro D
    7. Sellitto C
    8. Scarpa S
    9. Bellavia D
    10. Lattanzio G

    (1995) Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice

    The EMBO Journal 14:1932–1941.

    https://doi.org/10.1002/j.1460-2075.1995.tb07185.x

    • PubMed
    • Google Scholar
57. 1. Segaliny AI
    2. Brion R
    3. Mortier E
    4. Maillasson M
    5. Cherel M
    6. Jacques Y
    7. Le Goff B
    8. Heymann D

    (2015) Syndecan-1 regulates the biological activities of interleukin-34

    Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research 1853:1010–1021.

    https://doi.org/10.1016/j.bbamcr.2015.01.023

    • Google Scholar
58. 1. Semerad CL
    2. Christopher MJ
    3. Liu F
    4. Short B
    5. Simmons PJ
    6. Winkler I
    7. Levesque JP
    8. Chappel J
    9. Ross FP
    10. Link DC

    (2005) G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow

    Blood 106:3020–3027.

    https://doi.org/10.1182/blood-2004-01-0272

    • PubMed
    • Google Scholar
59. 1. Shamri R
    2. Xenakis JJ
    3. Spencer LA

    (2011) Eosinophils in innate immunity: an evolving story

    Cell and Tissue Research 343:57–83.

    https://doi.org/10.1007/s00441-010-1049-6

    • PubMed
    • Google Scholar
60. 1. Smith LT
    2. Hohaus S
    3. Gonzalez DA
    4. Dziennis SE
    5. Tenen DG

    (1996) PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells

    Blood 88:1234–1247.

    https://doi.org/10.1182/blood.V88.4.1234.bloodjournal8841234

    • PubMed
    • Google Scholar
61. 1. Stanley ER

    (2009) Lineage commitment: cytokines instruct, at last!

    Cell Stem Cell 5:234–236.

    https://doi.org/10.1016/j.stem.2009.08.015

    • PubMed
    • Google Scholar
62. 1. Styrt B

    (1989) Species variation in neutrophil biochemistry and function

    Journal of Leukocyte Biology 46:63–74.

    https://doi.org/10.1002/jlb.46.1.63

    • PubMed
    • Google Scholar
63. 1. Summers C
    2. Rankin SM
    3. Condliffe AM
    4. Singh N
    5. Peters AM
    6. Chilvers ER

    (2010) Neutrophil kinetics in health and disease

    Trends in Immunology 31:318–324.

    https://doi.org/10.1016/j.it.2010.05.006

    • PubMed
    • Google Scholar
64. 1. Takezaki N
    2. Nishihara H

    (2017) Support for lungfish as the closest relative of tetrapods by using slowly evolving Ray-finned fish as the outgroup

    Genome Biology and Evolution 9:evw288.

    https://doi.org/10.1093/gbe/evw288

    • Google Scholar
65. 1. Tanaka T
    2. Akira S
    3. Yoshida K
    4. Umemoto M
    5. Yoneda Y
    6. Shirafuji N
    7. Fujiwara H
    8. Suematsu S
    9. Yoshida N
    10. Kishimoto T

    (1995) Targeted disruption of the NF-IL6 gene discloses its essential role in Bacteria killing and tumor cytotoxicity by macrophages

    Cell 80:353–361.

    https://doi.org/10.1016/0092-8674(95)90418-2

    • PubMed
    • Google Scholar
66. 1. Tanaka T
    2. Narazaki M
    3. Kishimoto T

    (2014) IL-6 in inflammation, immunity, and disease

    Cold Spring Harbor Perspectives in Biology 6:a016295.

    https://doi.org/10.1101/cshperspect.a016295

    • PubMed
    • Google Scholar
67. 1. Umeda S
    2. Takahashi K
    3. Shultz LD
    4. Naito M
    5. Takagi K

    (1996)

    Effects of macrophage colony-stimulating factor on macrophages and their related cell populations in the osteopetrosis mouse defective in production of functional macrophage colony-stimulating factor protein

    The American Journal of Pathology 149:559–574.

    • PubMed
    • Google Scholar
68. 1. Ussov WY
    2. Aktolun C
    3. Myers MJ
    4. Jamar F
    5. Peters AM

    (1995) Granulocyte margination in bone marrow: comparison with margination in the spleen and liver

    Scandinavian Journal of Clinical and Laboratory Investigation 55:87–96.

    https://doi.org/10.3109/00365519509075382

    • PubMed
    • Google Scholar
69. 1. van Grinsven E
    2. Textor J
    3. Hustin LSP
    4. Wolf K
    5. Koenderman L
    6. Vrisekoop N

    (2019) Immature neutrophils released in acute inflammation exhibit efficient migration despite incomplete segmentation of the nucleus

    The Journal of Immunology 202:207–217.

    https://doi.org/10.4049/jimmunol.1801255

    • PubMed
    • Google Scholar
70. 1. van Raam BJ
    2. Drewniak A
    3. Groenewold V
    4. van den Berg TK
    5. Kuijpers TW

    (2008) Granulocyte colony-stimulating factor delays neutrophil apoptosis by inhibition of calpains upstream of caspase-3

    Blood 112:2046–2054.

    https://doi.org/10.1182/blood-2008-04-149575

    • PubMed
    • Google Scholar
71. 1. Wilkinson AN
    2. Gartlan KH
    3. Kelly G
    4. Samson LD
    5. Olver SD
    6. Avery J
    7. Zomerdijk N
    8. Tey SK
    9. Lee JS
    10. Vuckovic S
    11. Hill GR

    (2018) Granulocytes are unresponsive to IL-6 due to an absence of gp130

    The Journal of Immunology 200:3547–3555.

    https://doi.org/10.4049/jimmunol.1701191

    • PubMed
    • Google Scholar
72. 1. Yamanaka R
    2. Barlow C
    3. Lekstrom-Himes J
    4. Castilla LH
    5. Liu PP
    6. Eckhaus M
    7. Decker T
    8. Wynshaw-Boris A
    9. Xanthopoulos KG

    (1997) Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein -deficient mice

    PNAS 94:13187–13192.

    https://doi.org/10.1073/pnas.94.24.13187

    • Google Scholar
73. 1. Yáñez A
    2. Coetzee SG
    3. Olsson A
    4. Muench DE
    5. Berman BP
    6. Hazelett DJ
    7. Salomonis N
    8. Grimes HL
    9. Goodridge HS

    (2017) Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes

    Immunity 47:890–902.

    https://doi.org/10.1016/j.immuni.2017.10.021

    • Google Scholar
74. 1. Yates AD
    2. Achuthan P
    3. Akanni W
    4. Allen J
    5. Allen J
    6. Alvarez-Jarreta J
    7. Amode MR
    8. Armean IM
    9. Azov AG
    10. Bennett R
    11. Bhai J
    12. Billis K
    13. Boddu S
    14. Marugán JC
    15. Cummins C
    16. Davidson C
    17. Dodiya K
    18. Fatima R
    19. Gall A
    20. Giron CG
    21. Gil L
    22. Grego T
    23. Haggerty L
    24. Haskell E
    25. Hourlier T
    26. Izuogu OG
    27. Janacek SH
    28. Juettemann T
    29. Kay M
    30. Lavidas I
    31. Le T
    32. Lemos D
    33. Martinez JG
    34. Maurel T
    35. McDowall M
    36. McMahon A
    37. Mohanan S
    38. Moore B
    39. Nuhn M
    40. Oheh DN
    41. Parker A
    42. Parton A
    43. Patricio M
    44. Sakthivel MP
    45. Abdul Salam AI
    46. Schmitt BM
    47. Schuilenburg H
    48. Sheppard D
    49. Sycheva M
    50. Szuba M
    51. Taylor K
    52. Thormann A
    53. Threadgold G
    54. Vullo A
    55. Walts B
    56. Winterbottom A
    57. Zadissa A
    58. Chakiachvili M
    59. Flint B
    60. Frankish A
    61. Hunt SE
    62. IIsley G
    63. Kostadima M
    64. Langridge N
    65. Loveland JE
    66. Martin FJ
    67. Morales J
    68. Mudge JM
    69. Muffato M
    70. Perry E
    71. Ruffier M
    72. Trevanion SJ
    73. Cunningham F
    74. Howe KL
    75. Zerbino DR
    76. Flicek P

    (2020) Ensembl 2020

    Nucleic Acids Research 48:D682–D688.

    https://doi.org/10.1093/nar/gkz966

    • PubMed
    • Google Scholar
75. 1. Yoshida H
    2. Hayashi S
    3. Kunisada T
    4. Ogawa M
    5. Nishikawa S
    6. Okamura H
    7. Sudo T
    8. Shultz LD
    9. Nishikawa S

    (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene

    Nature 345:442–444.

    https://doi.org/10.1038/345442a0

    • PubMed
    • Google Scholar
76. 1. Yvan-Charvet L
    2. Ng LG

    (2019) Granulopoiesis and neutrophil homeostasis: a metabolic, daily balancing act

    Trends in Immunology 40:598–612.

    https://doi.org/10.1016/j.it.2019.05.004

    • PubMed
    • Google Scholar
77. 1. Zhang D-E
    2. Zhang P
    3. Wang N-d
    4. Hetherington CJ
    5. Darlington GJ
    6. Tenen DG

    (1997) Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein -deficient mice

    PNAS 94:569–574.

    https://doi.org/10.1073/pnas.94.2.569

    • Google Scholar
78. 1. Zhang P
    2. Nelson E
    3. Radomska HS
    4. Iwasaki-Arai J
    5. Akashi K
    6. Friedman AD
    7. Tenen DG

    (2002) Induction of granulocytic differentiation by 2 pathways

    Blood 99:4406–4412.

    https://doi.org/10.1182/blood.V99.12.4406

    • PubMed
    • Google Scholar
79. 1. Zhang P
    2. Iwasaki-Arai J
    3. Iwasaki H
    4. Fenyus ML
    5. Dayaram T
    6. Owens BM
    7. Shigematsu H
    8. Levantini E
    9. Huettner CS
    10. Lekstrom-Himes JA
    11. Akashi K
    12. Tenen DG

    (2004) Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha

    Immunity 21:853–863.

    https://doi.org/10.1016/j.immuni.2004.11.006

    • PubMed
    • Google Scholar
80. 1. Zimbelman J
    2. Thurman G
    3. Leavey PJ
    4. Ellison MC
    5. Ambruso DR

    (2002) In vivo treatment with granulocyte colony-stimulating factor does not delay apoptosis in human neutrophils by increasing the expression of the vacuolar proton ATPase

    Journal of Investigative Medicine 50:33–37.

    https://doi.org/10.2310/6650.2002.33515

    • PubMed
    • Google Scholar

Author details

1. Damilola Pinheiro

   Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft

   For correspondence

   d.pinheiro@imperial.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0294-9423

2. Marie-Anne Mawhin

   Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Visualization, Writing - review and editing

   Competing interests

   No competing interests declared

3. Maria Prendecki

   Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7048-7457

4. Kevin J Woollard

   Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Supervision, Methodology, Writing - review and editing

   For correspondence

   k.woollard@imperial.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9839-5463

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