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.

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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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