Cytokine 109 (2018) 76–80

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Cytokine
journal homepage: www.elsevier.com/locate/cytokine

Regulation of hematopoiesis by the chemokine system T

a a,b a a,b,c
Ornella Bonavita , Valeria Mollica Poeta , Matteo Massara , Alberto Mantovani ,
⁎
Raffaella Bonecchia,b,
a
Humanitas Clinical and Research Center, via Manzoni 56, 20089 Rozzano (MI), Italy
b
Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini, 20090 Pieve Emanuele (MI), Italy
c
The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK

A R T I C L E I N F O A B S T R A C T

Keywords: Although chemokines are best known for their role in directing cell migration, accumulating evidence indicate
Chemokines their involvement in many other processes. This review focus on the role of chemokines in hematopoiesis with an
Chemokine receptors emphasis on myelopoiesis. Indeed, many chemokine family members are an important component of the cy-
Hematopoiesis tokine network present in the bone marrow that controls proliferation, retention, and mobilization of hemato-
Myelopoiesis
poietic progenitors.

1. The chemokine system
Chemokines are a large family of chemotactic cytokines consisting
of more than 50 molecules. The name “chemo-kines” derives from their
capacity to cause chemotaxis in responsive cells, which express related
chemokine receptors. Chemokines have low amino acid sequence
homology, but they all have a conserved tertiary structure, consisting of
a disordered amino-terminus, three-stranded antiparallel β-sheet and a
carboxy-terminal α-helix [2].
Depending on the position of the cysteine residues in their N-ter-
minus, chemokines are divided in four subfamilies: CC, CXC, C and
CX3C [54,19]. The chemokine subfamilies CC, CXC and CX3C have four
well-conserved cysteine residues, which form two disulphide bonds
between the first and the third cysteine and between the second and the
fourth cysteine. The CC chemokines are the largest subfamily of che-
mokines and have the first two of the four cysteine residues in adjacent
position, while the CXC and CX3C chemokines have one and three
amino acids separating the two cysteines, respectively. The CXC che-
mokines can be further subdivided in ERL− and ERL+ chemokines,
based on the presence or absence of the ELR (Glu-Leu-Arg) motif [40].
In general, ERL− chemokines exhibit an anti-angiogenic activity,
whereas ERL+ chemokines are angiogenic factors [60,61]. Finally, the
XC subfamily is composed by only two chemokines having only two
cysteines in their sequence.
Based on their expression pattern, chemokines can be also classified
as homeostatic or inflammatory ones [34]. Homeostatic chemokines
(e.g. CXCL12, CXCL13, CCL14, CCL19) are constitutively produced and
regulate basal leukocyte trafficking, such us lymphocyte homing to
secondary lymphoid organs. Inflammatory chemokines (e.g. CCL2,
CCL5, CXCL8) are inducible molecules secreted during inflammatory
responses, upon infection or tissue injury and they drive leukocyte re-
cruitment to the site of inflammation.
The specific function of each chemokine is determined by the ex-
pression of chemokine receptors on target cells [5].Chemokine re-
ceptors are 7-transmembrane (7TM) receptors coupled to hetero-tri-
meric GTP-binding proteins (G-protein) of the Gi type, sensitive to
Bordetella pertussis toxin. Depending on the chemokines they bind,
chemokine receptors are classified as CXCR, CCR, CX3CR, or XCR and
can be either inflammatory or homeostatic [47].
Beyond canonical chemokine receptors, a smaller family of atypical
chemokine receptors (ACKRs) has been identified [4]. ACKRs share
many similarities with canonical chemokine receptors and bind ligands
with high affinity but show structural modifications in the motif that is
essential for G-protein interaction. As result, ACKRs are unable to
couple to G protein and to promote cell migration [8], and they act as
scavengers, transporters or depots for the chemokines they bind. The
family of ACKRs includes four receptors named ACKR1 (previously
called DARC), ACKR2 (D6), ACKR3 (CXCR7), and ACKR4 (CCX-CKR)
[4].
Most studies on chemokines and chemokine receptors were focused
on their ability to chemoattract leukocytes. However, it is known from
several years that chemokines regulate additional functions in leuko-
cytes. For instance, CXCR2 ligands regulate effector functions of neu-
trophils [6] and CCL19, acting on CCR7 expressed by dendritic cells,

Abbreviations: HSCs, hematopoietic stem cells; CMPs, common myeloid progenitors; GMPs, granulocytes-macrophages progenitors; ACKRs, atypical chemokine receptors; MEPs,
megakaryocyte-erythrocyte progenitors; HPCs, hematopoietic progenitor cells; NECs, nucleated erytrocyte precursors
⁎
Corresponding author at: Humanitas Clinical and Research Center, Humanitas University, Via Manzoni 56, 20089 Rozzano, Italy.
E-mail address: raffaella.bonecchi@hunimed.eu (R. Bonecchi).

https://doi.org/10.1016/j.cyto.2018.01.021
Received 16 October 2017; Received in revised form 19 January 2018; Accepted 24 January 2018
1043-4666/ © 2018 Elsevier Ltd. All rights reserved.
O. Bonavita et al.
regulates their survival [55]. Here, we resume data on the role of
chemokines in the control of differentiation, mobilization, and pro-
liferation of hematopoietic progenitors.
2. Hematopoiesis
Hematopoiesis is a dynamic process by which hematopoietic stem
cells (HSCs) proliferate and differentiate into mature blood cellular
components. HSCs are a rare population of cells characterized by an
extensive self-renewal capability and pluripotency. The division of
HSCs can result in the production of additional HSCs or hematopoietic
progenitor cells (HPCs), that have a limited self-renewal capability and
consist of cells in which multipotency is restricted [33,1,32].
In adult life, hematopoiesis takes place into the bone marrow (BM)
whereas during fetal development, since BM is not yet developed, liver,
thymus and spleen may assume hematopoietic function [7].
Histological analysis revealed that during adulthood, HSCs are
mainly located in restricted areas of BM, called as BM HSC niches
consisting of both hematopoietic and non-hematopoietic cell types. In
particular, HSCs are associated with cells of mesenchymal origin, si-
nusoidal endothelium, and with arterioles [20]. HSC niche represents a
complex microenvironment that provides the signals necessary to
maintain physiological homeostasis and to achieve the balance between
HSC renewal and differentiation. These signals can enhance or suppress
the growth, survival and movement of HSCs and progenitor cells. Ad-
hesion molecules such us P-selectin, E-selectin and vascular cell adhe-
sion molecules (VCAM-1) are expressed by niche stromal cells and
control HSC maintenance and function by the interaction with their
specific receptors on HSCs [41]. On the other hand, the niche elaborates
also many cytokines and growth factors, such as stem cell factor (SCF),
interleukin-3 (IL-3), interleukin-6 (IL-6) and colony-stimulating factors
(CSFs), that are essential for the initial rounds of cell division and dif-
ferentiation of HSCs [46]. As we will discuss below, an important player
in the interaction between HSCs and the niche is the CXCR4/CXCL12
axis [63].
3. Myelopoiesis
Myelopoiesis specifically refers to the process that leads to myeloid
cell production [7]. Myeloid cells derive from HSC differentiation into
common myeloid progenitors (CMPs) that are cells committed to the
myeloid lineage, and give rise to granulocyte-macrophage progenitors
(GMPs) and megakaryocyte-erythrocyte progenitors (MEPs). Next, the
differentiation of GMPs and MEPs gives rise to whole lineage of myeloid
cells, including monocytes, macrophages, granulocytes, platelets, ery-
throcytes, and dendritic cells (DCs) [33,1,32]. It has been demonstrated
in mice that tissue resident macrophages in liver (Kupffer cells), spleen
(red pulp macrophages), brain (microglia), epidermis (Langerhans
cells), lung (alveolar macrophages), peritoneum (large peritoneal
macrophages), pancreas, kidney and heart (F4/80bright macrophages)
originate from precursor cells in the yolk sac. They are long-lived and
can proliferate within their tissue of residence [35,66]. However, with
the exception of microglia, tissue resident macrophages are progres-
sively replaced by BM-derived progenitors throughout the lifespan of
the animal [52].
The cytokines of the colony stimulating factor (CSF) family are the
major orchestrators of myelopoiesis; they were defined by their abilities
to generate in vitro colonies of mature myeloid cells from BM precursor
cells, and they include: macrophage CSF (M-CSF; also known as CSF1),
which supports macrophage differentiation; granulocyte-macrophage
colony stimulating factor (GM-CSF; also known as CSF2), that stimulate
the proliferation and differentiation into monocytes and DCs; and
granulocyte colony stimulating factor (G-CSF; also known as CSF3),
which is important for the differentiation of neutrophil progenitors and
precursors [46]. However, within the microenvironment where HPCs
reside, they are likely influenced by a huge number of other cytokines,
77
Cytokine 109 (2018) 76–80
including chemokines.
4. Chemokines in hematopoiesis
The role of chemokines and their receptors in hematopoiesis en-
compasses the regulation of proliferation as well as the survival and the
retention of hematopoietic progenitors. In particular the CXCL12-
CXCR4 axis is fundamental for HSC homeostasis [30] and at least 24
chemokines belonging to CC, CXC and C families have been reported to
be endowed with myelosuppressive activity in vivo e in vitro
[17,28,37,14,67,10,11].
In this review, we seek to resume data on the main chemokines and
chemokine receptors that have been found involved in the regulation of
homeostatic hematopoiesis.
4.1. CXCL12-CXCR4 axis
The chemokine CXCL12, also known as stromal derived factor-1
(SDF-1), is a representative homeostatic chemokine and it is expressed
constitutively in the BM. CXCL12 is produced by a wide variety of cells
in the niche, including perivascular mesenchymal stromal cells (MSCs),
endothelial cells, osteoblasts, some hematopoietic cells, and by adipo-
genic progenitor cells with reticular shape [65,44]. The last cell type,
given its profuse production of CXCL12, is named CXCL12-abundant
reticular (CAR) cells and they are in close contact with HSCs. The
production of CXCL12 by these cells is fundamental for the homeostasis
of the hematopoietic niche [9]. Indeed, the binding of CXCL12 to the
receptor CXCR4, expressed on HSCs, induces their retention in the BM.
The relevance of the CXL12-CXCR4 axis is demonstrated by the fact that
the CXCR4 antagonist AMD3100 (Plerixafor) is an approved drug for
the mobilization of HSCs [22]. Moreover, the retention signal induced
by the CXCL12-CXCR4 axis is also the target of proteolytic enzymes,
such as Elastase, Cathepsin-G and CD26 that are known to induce HSC
mobilization. Indeed, it has been demonstrated that these enzymes
exert their mobilization activity by cleaving the N-terminal sequence of
CXCL12. These NH2-cleaved versions of CXCL12 are characterized by
decreased activity or even an antagonistic effect to the uncleaved
chemokine [46]. Interestingly, it was found that also G-CSF exerts its
HSC mobilization effect through neutrophil activation and release of
proteases, including MMP-9, that results in enhanced cleavage of c-kit,
CXCL12, CXCR4, VCAM-1 and its receptor Very Late Antigen-4 (VLA-4)
[62]. However, CXCL12 provides a retention signal for many other cells
expressing CXCR4 in the BM, including committed progenitors and
neutrophils [25].
In addition to control HSC retention in the BM, CXCL12 by inter-
acting with CXCR4, has other important effects on hematopoiesis and
myelopoiesis. This crucial role is corroborated by significant pheno-
typic changes in the hematopoietic system of mice lacking Cxcl12 or
Cxcr4 genes. These mice, that have a late gestation lethal phenotype
due to defective cardiac septum formation, have also defects in B-cell
lymphopoiesis and virtually absent BM myelopoiesis [39,31]. In addi-
tion, the deletion of one copy of CXCR4 is sufficient to give a selective
advantage for BM engraftment of HSCs. Indeed, Cxcr4 haploinsuffi-
ciency enhanced HSC proliferation while maintaining long-term he-
matopoiesis [43]. Furthermore, CXCL12 regulates HSC mitochondrial
respiration that is essential to maintain their undifferentiated state
[45]. These observations indicate that CXCL12, beside its role in BM
retention, has a role in keeping HSC quiescence, and maintaining a
constant pool of HSCs to sustain hematopoiesis.
Behind its direct effect on HSCs, CXCL12 can also indirectly have
impact on hematopoiesis. Studies in CXCR4-deficient mice have shown
that the CXCL12–CXCR4 axis, by regulating the development of vas-
culature, can have a crucial effect on the stucture of the hematopoietic
niche near the sinusoids [64].
O. Bonavita et al.
4.2. CCL3 and CCR1
In the context of hematopoiesis, CCL3/MIP-α is one of the best
studied chemokine. CCL3 was first identified as a suppressor molecule
for spleen colony formation units (CFU-s), and then for multi-growth
factor responding cells (CMP) [17,28]. Moreover, CCL3 can maintain a
quiescent state in HSCs by blocking cell cycle entry [17,13]. Interest-
ingly, it has been demonstrated that basophils in the BM are an im-
portant source of CCL3 and that upon BM transplantation, the genetic
deletion of Cccl3 gene in donor cells or the deletion of basophils, caused
exaggerated reconstitution of donor-derived hematopoietic cells. Be-
cause of its suppressive activity, CCL3 was suggested to act as a mye-
loprotective agent by placing HSCs and progenitors in a slowly cycle
state, that could be less sensitive to chemotherapy [3]. In addition using
Ccl3−/− mice it was recently demonstrated that this chemokine is es-
sential for the regulation of the proliferation of HSCs [59].
The receptor mediating CCL3 myelosuppressive effect is still uni-
dentified. Indeed, CCL3 is able to bind four chemokine receptors, CCR1,
CCR3, CCR5 and ACKR2 but none of the specific knock out mice re-
verted the CCL3 inhibitory function [50]. Thus, it is possible to spec-
ulate that the CCL3 myelosuppressive function is mediated by a still
unidentified receptor or by the combination of more than one known
receptors.
Even though CCR1 is not a dominant receptor for suppression of
CMPs and GMPs, it has been demonstrated to mediate the myelopoietic
effect of CCL3 on more mature myeloid progenitors [13]. Indeed, CCL3
enhances the proliferation of mature and committed myeloid progeni-
tors that respond to a single growth factor (CFU-G and CFU-M). How-
ever, the in vivo relevance of this effect is not understood because no
significant differences in CMPs and GMPs proliferation were observed
in CCR1 deficient versus WT mice [16,13].
CCL3, in addition to control the proliferation of myeloid progeni-
tors, regulates the mobilization of primitive progenitors with marrow
repopulating activity, by interacting mainly with CCR1 but not CCR5
[38].
4.3. CCR2 and its ligands
CCR2 is a dominant receptor for the suppression of myelopoiesis.
Indeed, mice lacking CCR2 showed increased cycling status of CMPs in
BM. Surprisingly, CCR2 deficiency did not affect the absolute number of
HPCs in BM and spleen compared to WT. This effect was due to the
control exerted by CCR2 on the proliferation and apoptosis of HPCs.
Indeed, Ccr2−/− HPCs showed a balance between enhanced prolifera-
tion and apoptosis [53]. The effect of CCR2 may be mediated by CCL2,
CCL13 as well as CCL12, since these CCR2 ligands, not CCL8 or CCL7,
are myelosuppressive [67].
CCR2, in addition to control the proliferation of CMPs, has a crucial
role in the mobilization of HSCs and mature myeloid cells, such as
monocytes and neutrophils, from BM to the peripheral blood. It has
been shown that during hematopoiesis, as HSCs differentiate along the
myeloid lineage, CCR2 expression increases and mediates also the
trafficking of HSCs, CMPs, and GMPs to the site of inflammation [57].
Interestingly, in various myeloid cell lines, CCR2 gene has been
identified as one of the several targets of G-CSF during neutrophilic
differentiation. Recently, CCR2 expression, which was previously sup-
posed to be restricted to monocytes, has been described in a subset of
murine BM neutrophils [29]. This expression has been demonstrated to
influence neutrophil egress from the BM. Indeed, analysis performed in
Ccr2-RFP+/− mice (with intact CCR2 expression) and Ccr2-RFP+/+
mice (CCR2 deficient) had shown that Ccr2-RFP+/+ mice have a small
but statistically significant decrease in the number of neutrophils in the
blood, LNs and spleen [27].
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Cytokine 109 (2018) 76–80
4.4. CCL5
The chemokine CCL5, appears to play a role in promoting myelo-
poiesis. Indeed, mice lacking CCL5 exhibited unbalanced hematopoi-
esis, having decreased myeloid progenitors and an increase in T cells
and lymphoid-biased HSCs. In contrast, overproduction of CCL5 by
retroviral expression in BM progenitors caused a deficit of T-cell output
concomitant with an increase in myeloid progenitors [26,68]. Since
high levels of the inflammatory chemokine CCL5 are found in the aging
hematopoietic niche, these observations suggest that aging-related
myeloid skewing phenotype, which may contribute to age-associated
immune deficiency, can result from increased expression of this che-
mokine. Since CCL5 binds four receptors, CCR1, CCR3, CCR5, and
ACKR2, at now it is not known which one is mediating the induction of
myeloid differentiation pathway.
4.5. CXCR2 and its ligands
Among CXC chemokines the CXCR2 ligands CXCL8, CXCL2 and the
murine homologs CXCL1 and CXCL2, were reported to inhibit the
proliferation of immature myeloid progenitors in vitro [12]. The mye-
losuppressive activity of these CXC chemokines has been assessed in
vivo by the use of gene targeted mice deleted for their receptor CXCR2.
In these mice, there is an expansion of CMPs, GMPs, and MEPs and
CXCL8 and CXCL2 do not inhibit their proliferation [12]. Moreover, in
mice lacking CXCR2 it was observed an increased number of mature
neutrophils, indicating that this receptor is also a regulator of neu-
trophil differentiation [18]. In addition, the myelosuppressive function
of CXCL8 was demonstrated also in the human system [15]. These re-
sults have been recently confirmed and extended by transcriptomic
analysis of human HSCs indicating that several CXC chemokines
(CXCL1-4, 6, 10, 11, and 13) are upregulated in human quiescent HSCs
compared to the proliferating one and that CXCR2 is required for the
HSC survival and self-renewal [58]. Thus, CXCR2 has been identified as
a negative regulator of HSCs, CMPs, GMPs, and MEPs proliferation by
mediating the suppressive activity of CXCL8 and CXCL2.
Several CXCR2 ligands, including CXCL1, CXCL2, and CXCL8 con-
trol also the mobilization of HPCs into peripheral blood in mice and
monkeys. However, it is not known if it is a direct effect on HSCs or an
indirect effect mediated by the neutrophil proteases on CXCL12 and
CXCR4 [51].
4.6. CXCL4
CXCL4, previously called platelet factor-4 (PF-4), is a CXC chemo-
kine produced by megakaryocytes and stored in platelet α-granules.
The release of CXCL4 by megakaryocytes, located near the sinusoids in
the BM, promotes HSC quiescence [49]. It was reported that CXCL4
induces quiescence by increasing the interaction between HPCs and the
chondroitin sulfate-containing moiety [24]. However, it is not known
whether CXCL4 can exert its suppressive function through interaction
with the chemokine CXCL8 or with the receptor CXCR3B [49].
4.7. The role of ACKRs
The study of ACKRs in hematopoiesis is just at its infancy but
emerging data indicate that they are important regulators of this pro-
cess. In a recent paper, Duchene et al. found that ACKR1, expressed by
BM nucleated erythroid cells (NECs), promotes their direct interaction
with HSCs. They demonstrated that this interaction is required for
physiological hematopoiesis because the lack of erythroid ACKR1 re-
sulted in decreased number of HPCs, altered differentiation, and neu-
trophil dysfunction [23,36]. These data give also explanation of the
neutropenia that characterizes healthy individuals of African ancestry
and is linked with one variant of the gene encoding ACKR1. However, it
is still unknown how ACKR1 is affecting HSCs, through the binding of
O. Bonavita et al.
chemokines or other chemokine receptors.
Another ACKR regulating hematopoiesis is ACKR2. Ackr2−/− mice
have increased number of circulating inflammatory monocytes [56],
and in humans a polymorphism of ACKR2 was reported to be linked to
altered number of circulating monocytes [21]. We have recently found
that Ackr2 deficiency in the hematopoietic compartment led to in-
creased myeloid differentiation of HPCs [42] indicating that ACKR2
may also regulate pathways involved in HPC differentiation.
Finally, ACKR3 is a high affinity receptor for CXCL12, a chemokine
highly involved in the homing and survival of HSCs in the BM (see
above). There are evidences indicating that ACKR3 modulates CXCR4
responses [48], but it is still unknown whether the CXCL12/ACKR3 axis
could regulate HSC biology.
5. Concluding remarks
It is now clear that in steady state conditions, members of chemo-
kine family play a central role in regulating hematopoiesis. They appear
to be central for the maintenance of the hematopoietic niche inducing
both the retention and the quiescence of HSCs. In particular, the CXC
chemokines CXCL12 and CXCL4 retain the progenitors inside the niche,
while the CXCR2 ligands CXCL2 and CXCL8 help keep the quiescent
state of HSCs. On the contrary, many CC chemokines have specific in-
hibitory effects on the myeloid lineage and, at the same time, they are
strong inducers of HPC mobilization. In this intricate picture (Fig. 1)
many informations are still lacking and a deeper investigation of the
system is required. Indeed, selective interference with these chemo-
kines and chemokine receptors could have important clinical implica-
tions for the treatment of many diseases and give rise to new treatment
modalities.
Acknowledgements
This study was supported by grants of the Italian Association for
Cancer Research, Italy (AIRC IG 15438 and 20269). The authors declare
no competing financial interests.
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Cytokine 109 (2018) 76–80
Fig. 1. Chemokine and chemokine receptors in-
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